Dihydronaphthalene derivative compounds and agent comprising the derivative as active ingredient

ABSTRACT

The compound 3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalene-1-yl)propanoic acid or a nontoxic salt thereof. Because this compound has activity of regulating peroxisome proliferators activated receptor regulator, it is useful as a hyperglycemic agent, a hypolipidemic agent, a preventative and/or treatment agent for diseases associated with metabolic disorders etc.

TECHNICAL FIELD

The present invention relates to dihydronaphthalene derivativecompounds.

More specifically, the present invention relates to

(1) dihydronaphthalene derivatives compounds represented by formula

(wherein all symbols have the same meanings as described below), ornontoxic salts thereof,

(2) a process for preparing thereof, and

(3) an agent comprising thereof as an active ingredient.

BACKGROUND ART

Recently in the study of transcription factors concerned with markergenes expression in adipocytes differentiation, peroxisome proliferatoractivated receptor (abbreviated as PPAR hereinafter), which is one ofintranuclear receptors, has been focused. cDNAs of PPAR were cloned fromvarious kinds of animals, and plural isoform genes were found,particularly in mammals three types of isoforms (α, δ, γ) are known (seeJ. Steroid Biochem. Molec. Biol., 51, 157 (1994); Gene Expression., 4,281 (1995); Biochem Biophys. Res. Commun., 224, 431 (1996); Mol.Endocrinology., 6, 1634 (1992)). PPAR γ isoform is predominantlyexpressed in adipose tissues, immune cells, adrenal gland, spleen, smallintestine. PPAR α isoform is mainly expressed in adipose tissue, liver,retina, and PPAR δ isoform is widely expressed without specificity fortissue (see Endocrinology., 137, 354 (1996)).

On the other hand, the following thiazolidine derivatives are known asagents for the treatment of non-insulin dependent diabetes mellitus(NIDDM) and are hypoglycemic agents which are used for the improvementof hyperglycemia in the patients suffering from diabetes. They are alsoeffective for the improvement of hyperinsulinemia, glucose tolerance anddecrease of serum lipid and therefore they are thought to beconsiderably hopeful as agents for the treatment of insulin resistance.

One of the target proteins in the cells of these thiazolidinederivatives is exactly PPAR γ and it is resolved that they enhance thetranscription activity of PPAR γ (see Endocrinology., 137, 4189 (1996);Cell., 83, 803 (1995); Cell., 83, 813 (1995); J. Biol. Chem., 270, 12953(1995)). Therefore, a PPAR γ activator (agonist) which enhances itstranscription activity is thought to be hopeful as a hypoglycemic agentand/or a hypolipidemic agent. Furthermore, since a PPAR γ agonist isknown to promote the expression of PPAR γ protein itself (Genes &Development., 10, 974 (1996)), an agent which increases the expressionof PPAR γ protein itself as well as PPAR γ activating agent is alsothought to be clinically useful.

PPAR γ is related to adipocytes differentiation (see J. Biol. Chem.,272, 5637 (1997) and Cell., 83, 803 (1995)). It is known thatthiazolidine derivatives which activate this receptor promote adipocytesdifferentiation. Recently it was reported that thiazolidine derivativesincrease fat mass and cause man to gain weight and to become obese (seeLancet., 349, 952 (1997)). Therefore, it is also thought thatantagonists which inhibit PPAR γ activity and agents that decrease theexpression of PPAR γ protein itself are also clinically applicable. Onthe other hand, a compound that phosphorylates PPAR γ protein anddecreases its activity is reported (Science., 274, 2100 (1996)). Thisimplies that an agent which does not bind on PPAR γ protein as a ligand,but inhibits its activity is also clinically applicable.

From these, PPAR γ activators (agonists) and PPAR γ regulators for itsexpression that can increase the expression of the protein itself areexpected to be useful as hypoglycemic agents, hypolipidemic agents, andagents for prevention and/or treatment of diseases associated withmetabolic disorders such as diabetes, obesity, syndrome X,hypercholesterolemia and hyperlipoproteinemia etc., hyperlipidemia,atherosclerosis, hypertension, circulatory diseases and overeating etc.

On the other hand, antagonists that inhibit the transcription activityof PPAR γ or PPAR γ regulators that inhibit the expression of theprotein itself are expected to be useful as hypoglycemic agents andagents for prevention and/or treatment of diseases associated withmetabolic disorders such as diabetes, obesity and syndrome X etc.,hyperlipidemia, atherosclerosis, hypertension and overeating etc.

The following fibrate compound (e.g. chlofibrate) is known as ahypolipidemic agent.

And, it is also resolved that one of the target proteins in the cells offibrate compounds is PPAR α (see Nature., 347, 645 (1990); J. SteroidBiochem. Molec. Biol., 51, 157 (1994); Biochemistry., 32, 5598 (1993)).From these facts, PPAR α regulators which can be activated by fibratecompounds are thought to have a hypolipidemic effect, and so they areexpected to be useful as agents for prevention and/or treatment ofhyperlipidemia etc.

Besides, it has been recently reported that PPAR α possesses anti-obeseactivity in the specification of WO 9736579. In addition, it wasreported that the elevation of high density lipoprotein (HDL)cholesterol level and the reduction of low density lipoprotein (LDL)cholesterol, very low density lipoprotein (VLDL) cholesterol andtriglyceride levels were induced by activation of PPAR α (J. Lipid Res.,39, 17 (1998)). It was also reported that composition of fatty acids inblood, hypertension and insulin resistance were improved byadministration of bezafibrate which is one of fibrate compounds(Diabetes., 46, 348 (1997)).

Therefore, agonists that activate PPAR α and PPAR α regulators thatpromote expression of PPAR α protein itself are useful as hypolipidemicagents and agents for treatment of hyperlipidemia, and are expected tohave HDL cholesterol level-elevating effect, LDL cholesterol and/or VLDLcholesterol levels-lowering effect, inhibition on the progress ofatherosclerosis and anti-obese effect. Therefore, they are thought to behopeful agents for the treatment and/or prevention of diabetes ashypoglycemic agents, for the improvement of hypertension, for the relieffrom risk factor of syndrome X and for the prevention of occurrence ofischemic coronary diseases.

On the other hand, few reports are found on ligands that activate PPAR δsignificantly or on biological activities associated with PPAR δ. PPAR δis sometimes called PPAR δ, or it is also called NUC1 in human. Untilnow, as for activity of PPAR δ, it is disclosed in the specification ofWO 9601430 that hNUC1B (PPAR subtype whose structure is different fromthat of human NUC1 in one amino acid) inhibited the transcriptionactivities of human PPAR α and thyroid hormone receptor. Recently in thespecification of WO 9728149, it was reported that the compounds, whichpossessed high affinity to PPAR δ protein and which could activate PPARδ significantly (i.e. agonists) were found out and that they had HDL(high density lipoprotein) cholesterol level-elevating activity.Therefore, agonists that can activate PPAR δ are expected to have HDLcholesterol level-elevating effect, and so they are expected to beuseful for the inhibition on the progress of atherosclerosis andtreatment thereof, as hypolipidemic agents and hypoglycemic agents, forthe treatment of hyperlipidemia, as hypoglycemic agents, for thetreatment of diabetes, for the relief from risk factor of syndrome X,and for the prevention of occurrence of ischemic coronary diseases.

For example, the specification of WO9828254 discloses that a compoundrepresented by formula (A)

(wherein, A^(A) is optionally substituted aryl or heterocyclic ring,X^(1A) is bond, O atom, etc., y^(1A) is optionally substituted C1–8alkylene, X^(2A) is bond, O atom, etc., W is optionally substitutednaphthalene, etc., B^(A) is carboxyl, etc., X^(3A) is O atom, etc.,R^(3A) is optionally substituted C1–8 alkyl, etc., nA is integer of1–4.)or a salt thereof has a hypoglycemic activity and a hypolipidemicactivity (necessary parts were extracted from the description ofgroups).

The specification of WO9911255 disclose that a compound of representedby formula (B)

(wherein, R^(1B) is C1–8 alkyl, etc., R^(2B) is —COOR^(3B) (in whichR^(3B) is hydrogen, or C1–4 alkyl.), A^(B) is C1–8 alkylene, etc., G^(B)is carbocyclic ring, or hetero ring (the above carbocyclic ring andhetero ring is optionally substituted by C1–8 alkyl, etc.), E^(1B) isC1–8 alkylene, etc., E^(2B) is —O—, etc., E³B is bond, etc., Cyc^(1B) issaturated, partially saturated or unsaturated carbocyclic ring, etc.) ora salt thereof has a modulating activity of peroxisome proliferatoractivated receptor (necessary parts were extracted from the descriptionof groups).

Also, in Example 3(35) in the above specification, the compound offormula (B-1) is disclosed.

DISCLOSURE OF THE INVENTION

In order to find a compound having a PPAR modulating activity, thepresent inventors have conducted intensive studies and found, as aresult, that the objects can be accomplished by the compound representedby formula (I), and thus the present invention has been accomplished.

The present invention relates to

(1) A dihydronaphthalene derivative compound represented by formula (I)

(wherein X represents (1) bond, or (2)C1–4 alkylene,

Y represents (1) —O—, or (2) —S—,

Z represents C1–4 alkylene,

A represents (1) —O—, or (2) —S—,

R¹ represents (1) COOR⁵, (2) CONH₂, (3) CONHOH, (4) CH₂OH, (5) CHO, (6)1H-tetrazol-5-yl, or (7) 3,5-dioxoisooxazolin-4-yl,

R⁵ represents (1) hydrogen, or (2)C1–8 alkyl,

R² and R³ each independently represents (1) hydrogen, (2) C1–8 alkyl,(3)

C1–8 alkoxy, or (4) C1–8 alkoxy substituted by a phenyl,

R⁴ represents (1) hydrogen, or (2) C1–8 alkyl,

D represents D¹, D², or D³,

D¹ represents

ring1 represents partially or fully optionally saturated C3–10 mono- orbi-carbocyclic aryl,

D2 represents

ring2 represents partially or fully optionally saturated 3–10 memberedmono- or bi-heterocyclic aryl containing 1–4 hetero atom(s) selectedfrom oxygen, nitrogen or sulfur atom,

D³ represents C1–8 alkyl,

R⁶ represents (1) hydrogen, (2) C1–8 alkyl, (3) nitro, (4) NR⁷R⁸, (5)halogen, (6) C1–8 alkoxy, (7) C1–8 alkylthio, (8) CF₃, (9) CF₃O, (10)partially or fully optionally saturated C3–10 mono- or bi-carbocyclicaryl, or (11) partially or fully optionally saturated 3–10 memberedmono- or bi-heterocyclic aryl containing 1–4 hetero atom(s) selectedfrom oxygen, nitrogen or sulfur atom, R⁷ and R⁸ each independentlyrepresents (1) hydrogen atom, or (2) C1-alkyl, m represents 1–3.)

or a nontoxic salt thereof,

(2) a process for preparing thereof, and

(3) an agent comprising thereof as an active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

In the specification, the C1–8 alkyl group includes methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, and octyl groups, and isomersthereof.

In the specification, the C1–4 alkylene group includes methylene,ethylene, trimethylene, and tetramethylene groups, and isomers thereof.

In the specification, the C1–5 alkylene group includes methylene,ethylene, trimethylene, tetramethylene, and pentamethylene groups, andisomers thereof.

In the specification, the C1–2 alkylene group includes methylene, andethylene groups, and isomers thereof.

In the specification, the C1–3 alkylene group includes methylene,ethylene, and trimethylene groups, and isomers thereof.

In the specification, the C2–3 alkylene group includes ethylene, andtrimethylene groups, and isomers thereof.

In the specification, the C1–8 alkoxy group includes methoxy, ethoxy,propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, and octyloxy groups,and isomers thereof.

In the specification, the halogen atom means a chlorine, bromine,fluorine or iodine atom.

In the specification, 1H-tetrazol-5-yl group means

In the specification, 3,5-dioxoisooxazolidin-4-yl group means

In the specification, partially or fully optionally saturated C3–10mono- or bi-carbocyclic aryl represented by ring1 and R⁶, means, forexample, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene,cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene,cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene,benzene, pentalene, azulene, perhydroazulene, perhydropentalene, indene,perhydroindene, indan, naphthalene, tetrahydronaphthalene,perhydronaphthalene, etc.

In the specification, among partially or fully optionally saturated 3–10membered mono- or bi-heterocyclic aryl containing 1–4 hetero atom(s)selected from oxygen, nitrogen or sulfur atom, 3–10 membered mono- orbi-heterocyclic aryl containing 1–4 hetero atom(s) selected from oxygen,nitrogen or sulfur atom means, for example, pyrrole, imidazole,triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene,thiine, thiepin, oxazole, isoxazole, thiazole, isothiazole, furazan,oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole,thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole,indolizine, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline,quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline,quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole,chromene, benzofurazan, benzothiadiazole, benzotriazole, etc.

Also, partially or fully saturated 3–10 membered mono- orbi-heterocyclic aryl containing 1–4 hetero atom(s) selected from oxygen,nitrogen or sulfur atom, means, aziridine, azetidine, pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,tetraazoline, tetraazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiin (dihydrothiopyran),tetrahydrothiin (tetrahydrothiopyran), dihydrothiepin,tetrahydrothiepin, perhydrothiepin, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isooxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiadiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dioxolane, dioxane, dithiolane, dithiane, dioxaindan, benzodioxane,chromane, benzodithiolane, benzodithiane, etc.

In the present invention, PPAR regulator includes all the regulators ofPPAR α, γ, δ, α+γ, α+δ, γ+δ and α+γ+δ. Preferable regulatory fashion is,PPAR α regulator, PPAR γ regulator, PPAR δ regulator, PPAR α+γregulator, PPAR α+δ regulator, more preferably PPAR α+γ regulator. PPARregulator also includes PPAR agonist and PPAR antagonist, preferablyPPAR agonist, more preferably PPAR α agonist, PPAR γ agonist, PPAR δagonist, PPAR α+γ agonist or PPAR α+δ agonist, particularly preferablyPPAR α+γ agonist.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkoxy and alkylene group includesstraight or branched ones. In addition, isomers on double bond, ring,fused ring (E—, Z—, cis-, trans-isomer), isomers generated fromasymmetric carbon atom(s) (R—, S—, α-, β-isomer, enantiomer,diastereomer), optically active isomers (D-, L-, d-, I-isomer), polarcompounds generated by chromatographic separation (more polar compound,less polar compound), equilibrium compounds, mixtures thereof atvoluntary ratios and racemic mixtures are also included in the presentinvention.

According to the present invention, unless otherwise indicated and as isapparent for those skilled in the art, symbol

indicates that it is bound to the opposite side of the sheet (namelyα-configuration), symbol

indicates that it is bound to the front side of the sheet (namelyβ-configuration), symbol

indicates that it is α-, β- or a mixture thereof, and symbol

indicates that it is a mixture of α-configuration and β-configuration.

The compound of the present invention can be converted into a nontoxicsalt by known methods.

A nontoxic salt is preferably pharmaceutically acceptable andwater-soluble.

A nontoxic salt means, for example, salts of alkali metals (e.g.,potassium, sodium, lithium, etc.), salts of alkaline earth metals (e.g.,calcium, magnesium, etc.), ammonium salts (e.g., tetramethylammonium,tetrabutylammmonium, etc.), salts of organic amines (e.g.,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine,N-methyl-D-glucamine, etc.), acid-addition salts (e.g., inorganic acidsalts (e.g., hydrochloride, hydrobromate, hydroiodate, sulfate,phosphate, and nitrate, etc.), organic acid salts (e.g., acetate,trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,benzoate, citrate, methane sulfonate, ethane sulfonate, benzenesulfonate, toluene sulfonate, isethionate, glucuronate, gluconate,etc.), etc.

Furthermore, a solvate of compound of the present invention representedby formula (I), and the above alkai (earth) metals, ammmonium, organicamines and acid-addition salts thereof, is included in the presentinvention.

The solvate is preferably nontoxic and water-soluble. Appropriatesolvates means, for example, solvates such as water, an alcohol solvent(e.g., ethanol, etc.), etc.

In the present invention, X is preferably bond or C1–4 alkylene group,and more preferably C1–4 alkylene group. The C1–4 alkylene is preferablymethylene (—CH₂—), ethylene (—(CH₂)₂—) or trimethylene (—(CH₂)₃—), andmore preferably methylene (—CH₂—).

In the present invention, Y is preferably —O— group or —S— group, andmore preferably —O— group.

In the present invention, Z is preferably methylene (—CH₂)— or ethylene(—(CH₂)₂—), and more preferably ethylene (—(CH₂)₂—).

In the present invention, R¹ is preferably COOR⁵ group, CH₂OH group,1H-tetrazol-5-yl group, and more preferably COOR⁵ group.

In the present invention, R² and R³ are preferably hydrogen atom, C1–8alkyl or C1–8 alkoxy, and more preferably hydrogen atom.

In the present invention, R⁴ is preferably C1–8 alkyl group, and morepreferably methyl group.

In the present invention, D is preferably D¹ or D², and more preferablyD¹.

In the present invention, A is preferably —O— group or —S— group, andmore preferably —O— group.

In the present invention, ring1 is preferably partially or fullyoptionally saturated C3–7 mono-carbocyclic aryl, and more preferablyC3–7 mono-carbocyclic aryl, and furthermore preferably benzene.

In the present invention, ring2 is preferably partially or fullyoptionally saturated 3–10 membered mono- or bi-heterocyclic arylcontaining 1–2 hetero atom(s) selected from oxygen, nitrogen or sulfuratom, and more preferably partially or fully optionally saturated 3–7membered mono-heterocyclic aryl containing 1–2 hetero atom(s) selectedfrom oxygen, nitrogen or sulfur atom, and furthermore preferablypyridine, tetrahydropyridine, piperidine, piperazine, thiomorpholine,morpholine, pyrazole, pyrazine, 1,3-dioxaindan.

Among the compounds represented by formula (I), preferred compounds arecompounds represented by formula (I-A)

(wherein all symbols have the same meanings as described above.),compounds represented by formula (I-B)

(wherein all symbols have the same meanings as described above.), andcompounds represented by formula (I-C)

(wherein all symbols have the same meanings as described above.).

Concrete compounds of the present invention include compounds shown inTables 1 to 13, compounds described in Examples, and nontoxic saltsthereof.

In each Table, Me represents methyl group, Et represents ethyl group, Prrepresents propyl group, i-Pr represents isopropyl group, t-Burepresents tertiarybutyl group, and other symbols have the same meaningsas described above.

TABLE 1 (I-A-1)

No R⁶ 1 H 2 Me 3 Pr 4 i-Pr 5 t-Bu 6 Cl 7

8

9

10

11

12 OCF₃ 13 CF₃ 14 NO₂ 15 NMe₂ 16 OMe 17 SMe 18

19

20

21

22

TABLE 2 (I-A-2)

No R⁶ 1 H 2 Me 3 Pr 4 i-Pr 5 t-Bu 6 Cl 7

8

9

10

11

12 OCF₃ 13 CF₃ 14 NO₂ 15 NMe₂ 16 OMe 17 SMe 18

19

20

21

22

TABLE 3 (I-A-3)

No R⁶ 1 H 2 Me 3 Pr 4 i-Pr 5 t-Bu 6 Cl 7

8

9

10

11

12 OCF₃ 13 CF₃ 14 NO₂ 15 NMe₂ 16 OMe 17 SMe 18

19

20

21

22

TABLE 4 (I-A-4)

No R⁶ 1 H 2 Me 3 Pr 4 i-Pr 5 t-Bu 6 Cl 7

8

9

10

11

12 OCF₃ 13 CF₃ 14 NO₂ 15 NMe₂ 16 OMe 17 SMe 18

19

20

21

22

TABLE 5 (I-B-1)

No R⁶ 1 H 2 Me 3 Pr 4 i-Pr 5 t-Bu 6 Cl 7

8

9

10

11

12 OCF₃ 13 CF₃ 14 NO₂ 15 NMe₂ 16 OMe 17 SMe 18

19

20

21

22

TABLE 6 (I-B-2)

No ring2 1

2

3

4

5

6

7

8

9

10

11

12

TABLE 7 (I-B-3)

No R⁶ 1 H 2 Me 3 Pr 4 i-Pr 5 t-Bu 6 Cl 7

8

9

10

11

12 OCF₃ 13 CF₃ 14 NO₂ 15 NMe₂ 16 OMe 17 SMe 18

19

20

21

22

TABLE 8 (I-B-4)

No ring2 1

2

3

4

5

6

7

8

9

10

11

12

TABLE 9 (I-B-5)

No R⁶ 1 H 2 Me 3 Pr 4 i-Pr 5 t-Bu 6 Cl 7

8

9

10

11

12 OCF₃ 13 CF₃ 14 NO₂ 15 NMe₂ 16 OMe 17 SMe 18

19

20

21

22

TABLE 10 (I-B-6)

No ring2 1

2

3

4

5

6

7

8

9

10

11

12

TABLE 11 (I-B-7)

No R⁶ 1 H 2 Me 3 Pr 4 i-Pr 5 t-Bu 6 Cl 7

8

9

10

11

12 OCF₃ 13 CF₃ 14 NO₂ 15 NMe₂ 16 OMe 17 SMe 18

19

20

21

22

TABLE 12 (I-B-8)

ring2 1

2

3

4

5

6

7

8

9

10

11

12

TABLE 13 (I-C-1)

No. D¹ A 1 Me —O— —O— 2 Et —O— —O— 3 Pr —O— —O— 4 i-Pr —O— —O— 5 t-Bu—O— —O— 6 Me —O— —S— 7 Et —O— —S— 8 Pr —O— —S— 9 i-Pr —O— —S— 10 t-Bu—O— —S— 11 Me —S— —O— 12 Et —S— —O— 13 Pr —S— —O— 14 i-Pr —S— —O— 15t-Bu —S— —O— 16 Me —S— —S— 17 Et —S— —S— 18 Pr —S— —S— 19 i-Pr —S— —S—20 t-Bu —S— —S—

(1) Among the compounds of the present invention represented by formula(I), a compound in which R¹ represents a COOR⁵ group, and R⁵ representsC1–8 alkyl group, i.e., a compound represented by formula (IA)

(wherein R⁵⁻¹ represents C1–8 alkyl group, and other symbols have thesame meanings as described above.) can be prepared by the followingmethods.

The compound represented by formula (IA) can be prepared by reacting acompound represented by formula (II)

(wherein R⁹ is represents a leaving group (e.g., a halogen atom, amesyloxy group or a tosyloxy group, etc.), D⁴ have the same meanings asD, with the proviso that the amino group included in the grouprepresented by D⁴ is protected if necessary. Other symbols have the samemeanings as described above.) with a compound represented by formula(III)

(wherein R¹⁰ represents OH group or SH group, and other symbols have thesame meanings as described above.), if necessary followed by subjectingto a deprotection reaction of protecting group.

This reaction is known. For example, it is carried out at 0 to 80° C. inan organic solvent (e.g., tetrahydrofuran (THF), diethyl ether,methylene chloride, chloroform, carbon tetrachloride, pentane, hexane,benzene, toluene, dimethylformamide (DMF), dimethylsulfoxide (DMSO),hexamethylphosphoramide (HMPA), etc.) in the presence of a base (e.g.,sodium hydride, potassium carbonate, triethylamine, pyridine, sodiumiodide, cesium carbonate, etc.).

The deprotection reaction of these protecting groups can be carried outby the following methods.

The deprotection reaction of these protecting groups of a amino group isknown, and examples include

-   (1) a deprotection reaction under acidic conditions,-   (2) a deprotection reaction by hydrogenolysis, and the like.

These methods are specifically described below.

(1) The deprotection reaction under acidic conditions is carried out,for example, in an organic solvent (e.g., methylene chloride,chloroform, dioxane, ethyl acetate, anisole, methanol, ethanol,isopropylalcohol, etc.) or absence of organic solvent or an aqueoussolution thereof, using an organic acid (e.g., acetic acid,trifluoroacetic acid, methanesulfonic acid, etc.), an inorganic acid(e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof(e.g., hydrogen bromide/acetic acid, etc.) at 0 to 100° C.

(2) The deprotection reaction by hydrogenolysis is carried out, forexample, in a solvent, (e.g., an ether system (e.g., tetrahydrofuran,dioxane, dimethoxyethane, diethyl ether, etc.), an alcohol system (e.g.,methanol, ethanol), a benzene system (e.g., benzene, toluene, etc.), aketone system (e.g., acetone, methyl ethyl ketone, etc.), a nitrilesystem (e.g., acetonitrile, etc.), an amide system (e.g.,dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixedsolvent of two or more of them, etc.), in the presence of a catalyst(e.g., palladium-carbon, palladium black, palladium hydroxide, platinumoxide, Raney nickel, etc.) under ordinary or forced pressure in anatmosphere of hydrogen or in the presence of ammonium formate at 0 to200° C.

Examples of the protecting group of an amino group include abenzyloxycarbonyl group, a t-butoxycarbonyl group, a trifluoroacetylgroup, and a 9-fluorenylmethoxycarbonyl group.

The protecting groups of an amino group is not particularly limited tothe above, and other groups can also be used, so long as they can beeasily and selectively released. For example, those which are describedby T. W. Greene in Protective Groups in Organic Synthesis, 3rd edition,Wiley, N.Y., 1999, can be used.

Although it can be easily understood by those skilled in the art, anobjective compound of the present invention can be easily prepared byproperly using these deprotection reactions.

Furthermore, among the compounds represented by formula (IA), a compoundin which Y represents —O— group, i.e., a compound represented by formula(IA-1)

(wherein all symbols have the same meanings as described above.) can beprepared by reacting a compound represented by formula (IV)

(wherein all symbols have the same meanings as described above.) with acompound represented by formula (III-1)

(wherein all symbols have the same meanings as described above.), ifnecessary followed by subjecting to a deprotection reaction ofprotecting group.

This reaction is known. For example, it is carried out by reacting witha corresponding alcohol compound in an organic solvent (e.g.,dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene,toluene, etc.) in the presence of an azo compound (e.g., diethylazodicarboxylate, diisopropyl azodicarboxylate,1,1′-(azodicarbonyl)dipiperidine, 1,1′-azobis(N,N-dimethylformamide),etc.) and a phosphine compound (e.g., triphenylphosphine,tributylphosphine, trimethylphosphine, etc.).

The deprotection reaction of a protecting group can be carried out bythe methods described above.

(2) Among the compounds represented by formula (I), a compound in whichR¹ represents COOH group, i.e., a compound represented by formula (IB)

(wherein all symbols have the same meanings as described above.) can beprepared by the following methods.

The compound represented by formula (IB) can be prepared by subjectingthe above compound represented by formula (A) to a hydrolysis reaction.

The said hydrolysis reaction is known. It is carried out, for example,

(1) in an organic solvent admissible with water (e.g., THF, dioxane,ethanol, methanol etc.) or mixture solvent thereof, using an aqueoussolution of alkali (e.g., potassium hydroxide, sodium hydroxide, lithiumhydroxide, potassium carbonate, sodium carbonate etc.), or

(2) in alkanol (e.g., methanol, ethanol etc.), using the above alkaliunder an anhydrous condition. These reactions may be carried out at0˜100° C. normally.

Also, among the compounds represented by formula (IB), a compound inwhich R² represents hydrogen atom, and R³ is C1–8 alkoxy group, i.e., acompound represented by formula (IB-1)

(wherein R³⁻¹ represents C1–8 alkoxy group, and other symbols have thesame meanings as described above.) can be prepared by subjecting acompound of formula (V)

(wherein all symbols have the same meanings as described above.) to ahydrolysis reaction, if necessary followed by subjecting to adeprotection reaction of protecting group.

This hydrolysis reaction is known. It is carried out, for example, in anorganic solvent admissible with water (e.g., (hydrous)methanol, dioxane,tetrahydrofuran, etc.) or mixture solvent thereof, in the presence of anaqueous solution of alkali (e.g., sodium hydroxide, potassium hydroxide,lithium hydroxide, etc.) at room temperature to reflux temperature.

The deprotection reaction of a protecting group can be carried out bythe methods described above.

(3) Among the compounds represented by formula (I), a compound in whichR¹ represents CH₂OH group, i.e., a compound represented by formula (IC)

(wherein all symbols have the same meanings as described above.) can beprepared by the following methods.

The compound represented by formula (IC) can be prepared by reduction ofa compound represented by formula (VI)

(wherein all symbols have the same meanings as described above.), ifnecessary followed by subjecting to a deprotection reaction ofprotecting group.

This reduction is known. For example, It is carried out in an organicsolvent (e.g., diethyl ether, tetrahydrofuran, toluene, methylenechloride, etc.) using a reductive agent (e.g., lithium aluminum hydride,diisobutylaluminum hydride, lithium borohydride, etc.) at −78 to 80° C.

The deprotection reaction of a protecting group can be carried out bythe methods described above.

(4) Among the compounds represented by formula (I), a compound in whichR¹ represents CHO group, i.e., a compound represented by formula (ID)

(wherein all symbols have the same meanings as described above.) can beprepared by the following methods.

The compound represented by formula (ID) can be prepared by reduction ofa compound represented by formula (VII)

(wherein all symbols have the same meanings as described above.), ifnecessary followed by subjecting to a deprotection reaction ofprotecting group.

This oxidation is known. For example, it includes the method

-   (1) by Swern oxidation,-   (2) using Dess-Martin Reagent,-   (3) using TEMPO Reagent.

These methods are explained as follows.

(1) Swern oxidation may be carried out, for example, by reacting oxalylchloride with dimethylsulfoxide in an organic solvent (e.g., chloroform,methylene chloride, etc.) at −78° C., and by reacting an obtainedintermediate with an alcohol compound, and then by reacting an obtainedcompound with a tertiary amine (e.g., triethylamine, etc.) at −78 to 20°C.

(2) The method using Dess-Martin Reagent may be carried out, forexample, in an inert organic solvent (e.g. chloroform, dichloromethane,etc.), using Dess-Martin Reagent(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol -3-(1H)-one) at 0 to 40°C.

(3) The method using TEMPO Reagent may be carried out, for example, inan inert organic solvent (e.g., chloroform, methylene chloride, etc.) inthe presence of TEMPO Reagent (2,2,6,6-tetramethyl-1-piperidinyloxy,free radical) at 20 to 60° C.

The reaction described in (1), (2) and (3) may be carried out under aninert gas (e.g. argon, nitrogen, etc.) to avoid water in order to obtaina preferable result.

As a method of oxidation, other methods, which can be oxidized alcoholto ketone easily and selectively, are also preferred, for example,Jone's oxidation, a method using pyridinium chlorochromate (PCC), amethod using sulfur trioxide pyridine complex or methods described inComprehensive Organic Transformations [Richard C. Larock, VCHPublishers, Inc., (1989) page 604–614].

The deprotection reaction of a protecting group can be carried out bythe methods described above.

(5) Among the compounds represented by formula (I), a compound in whichR¹ represents CONHOH group, i.e., a compound represented by formula (IE)

(wherein all symbols have the same meanings as described above.) can beprepared by the following methods.

The compound represented by formula (IE) can be prepared by subjecting acompound represented by formula (VII)

(wherein R¹¹ represents C1–8 alkyl substituted with phenyl group or C1–8alkoxy group, and other symbols have the same meanings as describedabove.) to a deprotection reaction of R¹¹ group, if necessary followedby subjecting to a deprotection reaction of protecting group.

The deprotection reaction of R¹¹ group (under acidic condition or byhydrogenolysis) is known. It can be carried out by the followingmethods.

The deprotection reaction under acidic conditions is known. For example,it is carried out, in an organic solvent (e.g., methylene chloride,chloroform, dioxane, ethyl acetate, anisole, etc.) using an organic acid(e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid,iodotrimethylsilane, etc.), an inorganic acid (e.g., hydrochloric acid,sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide aceticacid, etc.) at 0 to 100° C.

The deprotection reaction by hydrogenolysis is known. For example, it iscarried out in a solvent, (e.g., an ether system (e.g., tetrahydrofuran,dioxane, dimethoxyethane, diethyl ether, etc.), an alcohol system (e.g.,methanol, ethanol), a benzene system (e.g., benzene, toluene, etc.), aketone system (e.g., acetone, methyl ethyl ketone, etc.), a nitrilesystem (e.g., acetonitrile, etc.), an amide system (e.g.,dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixedsolvent of two or more of them, etc.), in the presence of a hydrogenatedcatalyst (e.g., palladium-carbon, palladium black, palladium, palladiumhydroxide, platinum oxide, nickel, Raney nickel, etc.), in the presenceof an inorganic acid (e.g., hydrochloric acid, sulfuric acid,hypochlorous acid, boric acid, tetrafluoroboric acid, etc.) or anorganic acid (e.g., acetic acid, p-toluenesulfonic acid, oxalic acid,tirfluoroacetic acid, formic acid, etc.) or absence thereof at 0 to 200°C. In the case that an acid is used, a salt of the acid may be used.

The deprotection reaction of a protecting group in D⁴ group can becarried out by the methods described above.

(6) Among the compounds represented by formula (I), a compound in whichR¹ represents 1H-tetrazol-5-yl group, i.e., a compound represented byformula (IF)

(wherein all symbols have the same meanings as described above.) can beprepared by the following methods.

The compound represented by formula (IF) can be prepared by reacting acompound represented by formula (IX)

(wherein all symbols have the same meanings as described above.) with anazido reagent, if necessary followed by subjecting to a deprotectionreaction of protecting group.

This reaction is known. For example, it is carried out at 50° C. toreflux temperature in an organic solvent (e.g., toluene, benzene, etc.)using an azido reagent (e.g., azidotrimethylthin, trimethylsilyl azide,sodium azide, etc.).

The deprotection reaction of a protecting group can be carried out bythe methods described above.

(7) Among the compounds represented by formula (I), a compound in whichR¹ represents 3,5-dioxoisooxazolin-4-yl group, i.e., a compoundrepresented by formula (IG)

(wherein all symbols have the same meanings as described above.) can beprepared by the following methods.

The compound represented by formula (IG) can be prepared by reacting acompound represented by formula (X)

(wherein R¹² represents C1–8 alkyl group, and other symbols have thesame meanings as described above.) with hydroxylamine, if necessaryfollowed by subjecting to a deprotection reaction of protecting group.

This reaction is known. For example, it is carried out by reacting withhydroxylamine at 0 to 50° C. in an organic solvent (e.g., methanol,ethanol, etc.) in the presence of a base (e.g., sodium methylate, sodiumethylate, etc.).

The deprotection reaction of a protecting group can be carried out bythe methods described above.

(8) Among the compounds represented by formula (I), a compound in whichR¹ represents CONH₂ group, i.e., a compound represented by formula (IH)

(wherein all symbols have the same meanings as described above.) can beprepared by the following methods.

The compound represented by formula (IH) can be prepared by amidation acompound represented by formula (XI)

(wherein all symbols have the same meanings as described above.) with anammonia, if necessary followed by subjecting to a deprotection reactionof protecting group.The amidation is known.

The amidation is known. It includes the method

-   (1) via an acyl halide,-   (2) via a mixed acid anhydride,-   (3) using a condensing agent, etc.

These methods are explained as follows.

(1) The method via an acyl halide may be carried out, for example, byreacting carboxylic acid with an acyl halide (e.g., oxalyl chloride,thionyl chloride, etc.) in an organic solvent (e.g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without asolvent at −20° C. to reflux temperature. And then the obtained acylhalide derivative may be reacted with amine in an inert organic solvent(e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran,etc.), in the presence of a tertiary amine (e.g., pyridine, triethylamine, dimethyl aniline, dimethylaminopyridine, etc.) at 0 to 40° C.

As an alternative, it may be carried out by reacting with an acyl halideat 0 to 40° C. in an organic solvent (e.g., dioxane, tetrahydrofuran,etc.) using an alkaline aqueous solution (e.g., sodium bicarbonate,sodium hydroxide, etc.) at 0 to 40° C.

(2) The method via a mixed acid anhydride may be carried out, forexample, by reacting carboxylic acid with an acyl halide (e.g., pivaloylchloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative(e.g., ethyl chloroformate, isobutyl chloroformate, etc.) in an organicsolvent (e.g., chloroform, methylene chloride, diethyl ether,tetrahydrofuran, etc.) or without a solvent, in the presence of atertiary amine (e.g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine, etc.), at 0 to 40° C. And then the obtained mixedacid anhydride derivative may be reacted with amine in an organicsolvent (e.g., chloroform, methylene chloride, diethyl ether,tetrahydrofuran, etc.), at 0 to 40° C.

(3) The method using a condensing agent may be carried out, for example,by reacting carboxylic acid with amine in an organic solvent (e.g.,chloroform, methylene chloride, dimethylformamide, diethyl ether,tetrahydrofuran, etc.), or a mixed solvent thereof, or without asolvent, in the presence or absence of a tertiary amine (e.g., pyridine,triethylamine, diisopropylethylamine, dimethylaniline,dimethylaminopyridine, etc.), using a condensing agent (e.g., 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1′-carbodiimidazole (CDl),2-chloro-1-methylpyridinium iodide, methyl 3-methyl-2-fluoropyridiniumtosylate, methanesulfonyloxybenzotriazole, 1-propanephosphonic acidcyclic anhydride (PPA), etc.), in the presence or absence of1-hydroxybenzotiazole (HOBt), at 0 to 40° C.

The reaction described in (1), (2) and (3) may be carried out under aninert gas (e.g. argon, nitrogen) to avoid water in order to obtain apreferable result.

The deprotection reaction of a protecting group can be carried out bythe methods described above.

The compounds represented by formulae (II) and (IV) are known compoundsor can be prepared easily by known methods or methods described inExamples.

For example, among the compounds of formula (IV),2-(5-methyl-2-phenyloxazol-4-yl)ethanol can be prepared by the methodsdescribed in J. Med. Chem., 35, 1853–1864(1992).

For example, among the compounds of formula (IV),2-(5-methyl-2-(morpholin-4-yl)oxazol-4-yl)ethanol can be prepared by themethods described in J. Med. Chem., 41, 5037–5054(1998).

The compounds represented by formulae (II), (III), (III-1), (IV), (V),(VIII), (IX) and (X) are known compounds or can be prepared easily byknown methods or methods described in Examples.

For example, the compounds represented by formulae (II), (III), (III-1),(IV), (V), (VIII), (IX) and (X) can be prepared by the methods shown bythe following Reaction Schemes 1 to 10.

In the reaction schemes, R¹³ represents a protecting group of hydroxygroup (e.g., methoxyethyl group, 2-tetrahydropyranyl group,t-butyidimethylsilyl group, acetyl group, benzyl group, 4-methoxybenzylgroup, pivaloyl group, etc.), R¹⁴ represents halogen atom, X¹ representsC1–5 alkylene group, X² representsC1–4 alkylene group, Me representsmethyl group, i-Pr represents isopropyl group, (CH₂O)_(n) representsparaformaldehyde, n-BuLi represents normalbutyllithium, Ph representsphenyl group, R²⁻¹ represents C1–8 alkyl group, R³⁻² represents C1–8alkyl group, LDA represents lithium diisopropylamide, R²⁻² representsC1–8 alkoxy substituted with a phenyl group, p-TsOH representsparatoluenesulfonic acid, TMSCN represents trimethylsilyl cyanide, Etrepresents ethyl group, Z¹ represents bond or C1–3 alkylene group, Z²represents C1–2 alkylene group, R⁴⁻¹ represents C1–8 alkylene group, Z³represents C2–3 alkylene group, and other symbols have the same meaningsas described above.

In Reaction Schemes, the compounds to be used as the starting materialsrepresented by formulae (XII), (XIV), (XVII), (XIX), (XX), (XXVIII),(XXXV), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXIII), (XXXXIV),(XXXXVI), (XXXXVII), (XXXXIX), (XXXXX), (XXXXXII), (XXXXXIX), (XXXXXXI),(XXXXXXII) and (XXXXXXIV) are known compounds or can be prepared easilyby known methods.

In each reaction described herein, the reaction product can be purifiedby general purification techniques such as distillation under ordinarypressure or a reduced pressure, high performance liquid chromatography,thin layer chromatography or column chromatography using silica gel ormagnesium silicate, washing and recrystallization. Purification may becarried out in each reaction or after completion of several reactions.

[Pharmacological Activity]

It was confirmed that compounds of the present invention of formula (I)has PPAR regulating activities by the following experiments.

Measurement of PPAR α Agonistic and PPAR γ Agonistic Activities

(1) Preparation of Materials in Luciferase Assay Using Human PPAR α or γ

The whole operations were carried out by the basic methods in geneengineering techniques and the conventional methods in yeast One-hybridor Two-hybrid system.

As a luciferase gene expression vector under the control of thymidinekinase (TK) promotor, luciferase structural gene was excised fromPicaGene Basic Vector 2 (trade name, Toyo Ink Inc., catalogue No.309-04821), to prepare luciferase gene expression vector pTK-Luc. underthe control of TK promotor (−105/+51) as a minimum essential promotoractivity from pTKβ having TK promotor (Chrontech Inc., catalogue No.6179-1). In the upper stream of TK promotor, four times repeated UASsequence was inserted, which is the response element of Gal4 protein, abasic transcription factor in yeast, to construct 4 X UAS-TK-Luc. asreporter gene. The following is the enhancer sequence used (SequenceNo.1).

Sequence No. 1: Enhancer sequence repeating Gal4 response elementfour-times tande mly.

5′-T(CGACGGAGTACTGTCCTCCG)x4 AGCT-3′

A vector was prepared as described hereafter which expresses chimericreceptor protein wherein in carboxy terminus of yeast Gal4 protein DNAbinding domain was fused to ligand binding domain of human PPAR α or γ.That is to say, PicaGene Basic Vector 2 (trade name, Toyo Ink Inc.,catalogue No. 309-04821) was used as a basic expression vector, thestructural gene was exchanged for that of chimeric receptor protein,while promotor and enhancer domains were kept as they were.

DNA encoding a fused protein composed of Gal4 DNA binding domain, the1st to 147th amino acid sequence linked to the ligand binding domain ofhuman PPAR α or γ in frame was inserted to the downstream ofpromotor/enhancer in PicaGene Basic Vector 2 (trade name, Toyo Ink Inc.,catalogue No. 309-04821). Here the DNA was aligned as follows; in theamino terminus of human PPAR α or γ ligand binding domain, nucleartranslocation signal originated from SV-40 T-antigen, Ala Pro Lys LysLys Arg Lys Val Gly (sequence No. 2) was added to make fusion proteinlocalizing intranuclearly. On the other hand, in the carboxy terminus ofthem, influenza hemagglutinin epitope, Tyr Pro Tyr Asp Val Pro Asp TyrAla (sequence No. 3) and stop codon for translation was added in thisorder, to detect an expressed fused protein tagged epitope sequence.

According to the comparison of human PPAR structures described in theliteratures by R. Mukherjee at al. (See J. Steroid Biochem. Molec.Biol., 51, 157 (1994)), M. E. Green et al., (See Gene Expression., 4,281 (1995)), A. Elbrecht et al. (See Biochem Biophys. Res. Commun., 224,431 (1996)) or A. Schmidt et al. (See Mol. Endocrinology., 6, 1634(1992)), the portion of structural gene used as ligand binding domain ofhuman PPAR α or γ was DNA encoding the following peptide:

human PPAR α ligand binding domain: Ser¹⁶⁷-Tyr⁴⁶⁸

human PPAR γ ligand binding domain: Ser¹⁷⁶-Tyr⁴⁷⁸

(each human PPAR γ1 ligand binding domain and human PPAR γ2 ligandbinding domain is Ser²⁰⁴-Tyr⁵⁰⁶ which is identical sequence each other).

In order to measure basal level of transcription, an expression vectorcontaining DNA binding domain of Gal4 protein lacking in PPAR ligandbinding domain, which is exclusively encoding the 1st to 147th aminoacid sequence in Gal4 protein was also prepared.(2) Luciferase Assay Using Human PPAR α or γ

CV-1 cells used as host cells were cultured by a conventional technique.That is to say, Dulbecco's modified Eagle medium (DMEM) supplemented 10%bovine fetal serum (GIBCO BRL Inc., catalogue No. 26140-061) and 50 U/mlof penicillin G and 50 μg/ml of streptomycin sulfate were used toculture CV-1 cells under the atmosphere of 5% carbon dioxide gas at 37°C.

2×10⁶ cells were seeded in a 10 cm dish, and once washed with the mediumwithout serum, followed by addition of the medium (10 ml) thereto.Reporter gene (10 μg), Gal4-PPAR expression vector (0.5 μg) and 50 μl ofLipofectAMINE (GIBRO BRL Inc., catalogue No.18324-012) were well mixedand added to the culture to introduce these DNAs into the host cells.They were cultured at 37° C. for 5˜6 hours, and thereto was added 10 mlof medium containing 20% of dialyzed bovine fetal serum (GIBRO BRL Inc.,catalogue No. 26300-061), and then cultured at 37° C. overnight. Thecells were dispersed by trypsin, and they were again seeded in 96-wellplates in a density of 8000 cells/100 ml of DMEM-10% dialyzedserum/well. Several hours after the cultivation, when cells wereattached to the plastic ware, then 100 μl of DMEM-10% dialyzed serumcontaining the compounds of the present invention, whose concentrationis twice as high as the final concentration of them, was added thereto.The culture was settled at 37° C. for 42 hours and the cells weredissolved to measure luciferase activity according to manufacturer'sinstruction.

As to PPAR α agonistic activity, the relative activity of the compoundsof the present invention (10 μM) was shown in Table 1, under thecondition that luciferase activity was defined as 1.0 in case ofcarbacyclin (10 μM) as a positive control compound, which could activatetranscription of luciferase gene significantly to PPAR α (See Eur. J.Biochem., 233, 242 (1996); Genes & Development., 10, 974 (1996)).

As to PPAR γ agonistic activity, the relative activity of the compoundsof the present invention (10 μM) was shown in Table 2, under thecondition that luciferase activity was defined as 1.0 in case oftroglitazone (10 μM) as a positive control compound, which couldactivate transcription of luciferase gene significantly to PPAR γ (SeeCell., 83, 863 (1995); Endocrinology., 137, 4189 (1996) and J. Med.Chem., 39, 665 (1996)) and has been already launched as hypoglycemicagent.

Furthermore, assay of each compound was carried out three times toexamine its reproducibility and to confirm the dose dependent activity.

Also, the following compound described in Example 3(35) in thespecification of WO9911255 was used as a comparative compound.

Compound Described in Example 3(35) in the Specification of WO9911255

TABLE 14 Relative Activity to a positive control compound Compound No.(carbacyclin = 1) Example 2 0.45 comprative 0.01 compound

TABLE 15 Relative Activity to a positive control compound Compound No.(troglitazone = 1) Example 2 2.6 comprative 0.004 compound

For example, Hypoglycemic and hypolipidemic effects of the compounds ofthe present invention can be measured by the following methods.

Hypoglycemic and Hypolipidemic Effects (1):

Male, 8-weeks old KKAy/Ta Jcl mice (five mice per group) are pre-breadedindividually in single cages for approximately one week and providedpellet diet and tap water from bottle of feed water ad libitum. Mice areacclimatized to switch over to milled diet for three days. On the firstday of the experiment (Day 0), the body weight of mice are measured.Blood samples are collected from coccygeal vein using a microcapillaryto measure plasma glucose concentration. Based on plasma glucoseconcentration, mice are divided into some groups (five mice per group)using a stratified randomization method. The body weight of mice aremeasured on the morning of the next day, and from the next day for sixdays they are given compounds by food mixture containing 0.03% (w/w),0.01% (w/w) or 0.003% (w/w) of the compound of the present invention orby milled diet only. On the morning of the fourth and the seventh day,body weights and food intakes of them are determined to calculate themean administered dose. On the morning of the sixth day, blood sampleswere collected from coccygeal vein to measure glucose and triglyceride(TG) levels. On the seventh day after measuring body weight, bloodsamples are collected from abdominal vena cava under anesthetizedcondition by ether to determine plasma insulin, non-esterified fattyacid (NEFA), GOT and GPT levels using commercially available kits. And,the liver is removed and weighed. The total RNAs are prepared from leftlobe of the liver and measured a gene expression level of bifunctionalprotein (hydrase-dehydrogenase, HD) by Northern blot method. Actually,there is no significant difference in the food intake between controlgroup (milled diet only) and compounds-treated group (milled dietcontaining 0.03%, 0.01% or 0.003% of compounds). The calculated dose isapproximately 40 mg/kg/day in the group given diet containing 0.03% ofthe compound.

It is suggested the possibility as an agent for preventing and/ortreating of diabetes mellitus, hyperlipidemia, atherosclerosis etc.,from ameliorating effects of plasma glucose, plasma insulin, NEFA or TGlevels in well-fed KKAy/Ta mice. This effect is likely to be mediatedthrough PPAR γ activation in vivo. Additionally, it is likely that anincrease in liver weight and in an expression of HD mRNA depends on PPARα activation in vivo.

Hypoglycemic and Hypolipidemic Effects (2):

Male, 8-weeks old Zucker fa/fa rats (Strain: Crj-[ZUC]-fa/fa) andhealthy Zucker lean rats (Strain: Crj-[ZUC]-lean) to be contrasted arepre-breaded individually in single cages for approximately two weeks andprovided pellet diet and tap water from automatic water supplyingequipment ad libitum. For five days before the treatment, rats areacclimatized to oral gavage administration. During this period, ageneral condition of them is observed, and healthy rats with 10-weeks ofage are used for experiment. The body weight of each rats are measuredon the morning of the first day of experiment (Day 0) and blood samplesare collected from coccygeal vein using a microcapillary to measureplasma glucose, TG, NEFA concentrations and HbA1c. Based on the HbAlcand body weight, rats are assigned to groups comprised of five animalseach using a stratified randomization method. Additionally, rats areinterchanged optionally to prevent the deflection of other parameters'averages between groups. The body weight of each animal was measuredevery morning from the day after grouping. Volumes to be administeredare calculated on the basis of body weight measured on the day ofadministration, and oral gavage administration of compound of thepresent invention or vehicle only (0.5% methylcellulose) is conductedonce a day for 13 days. The healthy animals (lean rats)are given vehicleonly.

Food consumption is measured on the morning of Day 1, 4, 7, 10 and 13 tocalculate mean food intakes. On the seventh day, blood samples arecorrected from coccygeal vein using microcapillary to measure plasmaglucose, TG, NEFA concentrations and HbA1c. And on the 14th day, oralglucose tolerance test (OGTT) is performed to evaluate improving effecton glucose intolerance. Rats are fasted on the previous day (Day 13) toperform OGTT. After blood samples are collected on the next day (Day14), 40% glucose solution is loaded at a volume of 2 g/5 ml/kg per oraladministration. 60 and 120 minutes after loading, blood samples arecollected from coccygeal vein using microcapillary to determine plasmaglucose levels.

Animals are given food after the OGTT and administered compound of thepresent invention on Day 15. On the morning of the 16th day aftermeasuring body weight, blood samples are collected from abdominal venacava under anesthetized condition by ether to determine plasma glucose,plasma insulin, TG, NEFA, GOT and GPT levels. And, the liver is removedand weighed.

It is suggested the possibility as an agent for preventing and/ortreating of diabetes mellitus, hyperlipidemia, atherosclerosis etc.,from ameliorating effects of plasma glucose, plasma insulin, TG, NEFAlevels or HbA1c in well-fed Zucker fa/fa rats. Also, a decrease effectof fasting plasma glucose and improving effect of glucose intoleranceduring OGTT suggest the possibility as an agent for preventing and/ortreating of diabetes mellitus. These effects are likely to be mediatedthrough PPAR γ activation in vivo. Additionally, it is suggested that anincrease in liver weight depends on PPAR α activation in vivo.

Hypoglycemic and Hypolipidemic Effects (3):

Male, 3- to 4-years old cynomolgus monkeys (Mean body weight:approximately 3 kg) to have a regal medical inspection are performed amedical inspection and acclimatized to be provided approximately 100 gof pellet diet once a day and tap water from automatic water supplyingequipment ad libitum, individually in single monkey cages for more thanone month. After then, animals become to take a diet within one hour.

Additionally, animals are pre-breaded for 14 days. 14 and 7 days beforethe treatment, the body weight are measured, and then blood samples arecollected from hindlimb saphenous vein to measure hematological (redblood cells, hematocrit, hemoglobin, platelet and leukocytes) andbiochemical (GOT, GPT, alkaline phosphatase, total protein, blood ureanitrogen, creatinine, creatinine kinase, total bilirubin, glucose, totalcholesterol, HDL, LDL and TG) parameters. Additionally, a generalcondition of animals is observed during acclimatizing and pre-breeding,and healthy animals are used for experiment. Also, food consumption ismeasured everyday.

On the basis of body weight measured on the final day of acclimatizingperiod, animals are divided into some groups (three animals per group)using a stratified randomization method. On the morning of Day 1, 3, 7,10 and 14, body weight is measured. Volumes to be administered arecalculated based on the latest body weight, and oral gavageadministration with compound of the present invention (3–100 mglkg/day)or vehicle alone (diluted solution) is conducted once a day for 14 days.1, 7 and 14 days after the treatment, blood samples are collected tomeasure the above mentioned hematological and biochemical parametersbefore the administration of the compound of the present invention. Itconfirms that blood glucose is not changed with the compound of thepresent invention. Three weeks before, and 14 days after the start oftreatment, blood samples are collected from hindlimb saphenous vein orantebrachial vein at 1, 2 and 4 hours after oral gavage, and also at 1,2 and 3 hours after providing a diet, to measure plasma glucose and TG.

It is suggested the possibility as an agent for preventing and/ortreating of hyperlipidemia and atherosclerosis etc., from amelioratingeffects of plasma TG levels in fasted monkeys. These effects are likelyto be mediated through PPAR α activation in vivo. It is also observed insuppressing effect on post-prandial TG increase. Additionally, it can beestimated whether compound have a toxicity risk from other biochemicalparameters.

[Toxicity]

The toxicity of the compound represented by formula (I) of the presentinvention is very low so that it is considered that the compound issufficiently safe for using as a pharmaceutical.

INDUSTRIAL APPLICABILITY

[Application to Pharmaceutical]

Since the compound represented by formula (I) of the present inventionand nontoxic salt thereof have a PPAR modulating activity, it isexpected to be applied as hypoglycemic agents, hypolipidemic agents,agents for preventing and/or treating of diseases associated withmetabolic disorders such as diabetes, obesity, syndrome X,hypercholesterolemia and hyperlipoproteinemia etc., hyperlipidemia,atherosclerosis, hypertension, circulatory diseases, overeating,coronary heart diseases etc., HDL cholesterol-elevating agents, LDLcholesterol and/or VLDL cholesterol-lowering agents and agents forrelieving risk factors of diabetes or syndrome X.

Also, since the compound represented by formula (I) of the presentinvention, and non-toxic salts thereof, have a PPARα agonist and/or PPARγ agonist effect, it is expected to be applied as hypoglycemic agents,hypolipidemic agents, agents for preventing and/or treating of diseasesassociated with metabolic disorders such as diabetes, obesity, syndromeX, hypercholesterolemia, hyperlipoproteinemia etc., hyperlipidemia,atherosclerosis, hypertension, circulatory diseases and overeating etc.,HDL cholesterol-elevating effect, LDL cholesterol and/or VLDLcholesterol-lowering effect, inhibition of progress of atherosclerosisand its treatment, and inhibitory effect against obesity. They are alsoexpected to be useful for the treatment and/or prevention of diabetes ashypoglycemic agents, for the amelioration of hypertension, for therelief from risk factors of syndrome X, and as agents for preventingagainst occurrence of coronary heart diseases.

For the purpose above described, the compounds of the present inventionof the formula (I) and non-toxic salts thereof may be normallyadministered systemically or locally, usually by oral or parenteraladministration.

The compound represented by formula (I) of the present invention, and anontoxic salt thereof is generally administered systemically ortopically and orally or parenterally when it is used for the aboveobjects.

The dosages are determined depending on age, body weight, symptom,therapeutic effect, administration route, duration of the treatment andthe like. Generally, 1 mg to 1000 mg per adult is orally administeredonce to several times per day, or 1 mg to 100 mg per adult isparenterally administered (preferably by intravenous administration)once to several times per day, or continuously administered from veinfor 1 to 24 hours per day.

Since the dose changes depending on various conditions as describedabove, there are cases in which doses lower than or greater than theabove ranges may be used.

The compound represented by formula (I) of the present invention may beadministered in the form of solid compositions, liquid compositions andother compositions for oral administration, and injections, liniments,suppositories and the like for parenteral administration.

Solid compositions for oral administration include tablets, pills,capsules, dispersible powders, granules and the like.

Capsules include hard capsules and soft capsules.

In such solid compositions, one or more active compound(s) are mixedwith at least one inert diluent such as lactose, mannitol, glucose,hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium metasilicate aluminate. The composition mayalso contain additional substances other than the inert diluent, e.g.,lubricants such as magnesium stearate, disintegrating agents such ascellulose calcium glycolate, stabilizing agents such as lactose, andassisting agents for dissolving such as glutamic acid and asparatic acidaccording to usual methods. If necessary, the tablets or pills may becoated with film of gastric- or enteric-coating agents such as sugar,gelatin, hydroxypropyl cellulose and hydroxypropyl cellulose phthalate,or be coated with two or more films. Furthermore, capsules of absorbablematerials such as gelatin are included.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, syrups, elixirs and the like. In suchliquid compositions, one or more active compound(s) are contained in aninert diluent commonly used (e.g., purified water, ethanol).Furthermore, such compositions may also contain auxiliary material suchas wetting agents or suspending agents, sweetening agents, flavoringagents, flavoring agents, and preserving agents.

Other compositions for oral administration include sprays containing oneor more active compound(s) which are prepared by known methods. Suchcompositions may contain stabilizing agents such as sodium hydrogensulfate, buffering agents to give isotonicity, isotonic solutions suchas sodium chloride, sodium citrate or citric acid, in addition to inertdiluents. The process for preparing sprays are described in U.S. Pat.Nos. 2,868,691 and 3,095,355.

Injections for parenteral administration in the present inventioninclude sterile aqueous or non-aqueous solutions, suspensions andemulsions. Aqueous solutions and suspensions include distilled water forinjection and physiological saline. Non-aqueous solutions andsuspensions include propylene glycol, polyethylene glycol, plant oilsuch as olive oil, alcohols such as ethanol, POLYSORBATE80 (registeredtrade mark), and the like. Sterile aqueous and non-aqueous solutions,suspensions and emulsions may be used as a mixture. Such compositionsmay further contain preserving agents, wetting agents, emulsifyingagents, dispersing agents, stabilizing agents (e.g., lactose), auxiliaryagents such as solubilizing auxiliary agents (e.g., glutamic acid,aspartic acid). They may be sterilized by filtration through abacteria-retaining filter, incorporation of a sterilizing agent orirradiation. For example, they may also be manufactured in the form ofsterile solid compositions which can be dissolved in sterile water orother sterile diluent for injection before use of the freeze-driedproduct.

Other compositions for parenteral administration include liquids forexternal use, endemic liniments, ointments, suppositories forintrarectal administration, pessaries for intravaginal administrationand the like containing one or more active compound(s) which can beprepared by known methods.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained below in detail based on ReferenceExamples and Examples, however, the present invention is not limitedthereto.

The solvents in the parentheses show the developing or eluting solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC. The solvents in the parentheses in NMR show thesolvents for measurement.

REFERENCE EXAMPLE 1 3-(5-hydroxy-3,4-dihydronaphthalen-1-yl)propanoicacid

To pyridine hydrochloride (200 g),3-(5-methoxy-3,4-dihydronaphthalen-1-yl)propanoic acid (25.1 g; knowncompound (see J. Chem. Soc. Perkin Trans. I., 1739–1742(1987)) wasadded, followed by stirring at 180° C. for 3 hours. The reaction mixturewas cooled to room temperature, and diluted with water. The aqueouslayer was acidified with a concentrated hydrochloric acid. The aqueouslayer was extracted with an ethyl acetate. The extract was extractedwith a saturated aqueous sodium hydrogen carbonate solution. Thecombined aqueous layer was acidified with a concentrated hydrochloricacid, followed by extracting with an ethyl acetate. The combined organiclayer was washed with a saturated saline, dried with anhydrous sodiumsulfate, and concentrated under reduced pressure to thereby obtain thetitle compound (11.8 g) having the following physical data.

TLC: Rf 0.42 (chloroform:methanol=6:1); NMR(CDCl₃): δ 9.21(s, 1H),6.98(dd, J=7.8, 7.6 Hz, 1H), 6.71(d, J=7.6 Hz, 1H), 6.70(d, J=7.8 Hz,1H), 5.82(t, J=4.4 Hz, 1H), 2.68–2.50(m, 4H), 2.36(m, 2H), 2.12(m, 2H).

REFERENCE EXAMPLE 2 3-(5-hydroxy-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

An anhydrous methanol (40 ml) was cooled to −10° C., and thionylchloride (5.92 ml) was added dropwise thereto under argon atmosphere,followed by stirring at −10° C. for 20 minutes. To this solution, thecompound (11.8 g) prepared in Reference Example 1 was added, followed bystirring at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure, followed by subjecting to azeotropywith toluene (twice). The residue was purified by silica gel columnchromatography (chloroform to chloroform:methanol=50:1) to therebyobtain the title compound (10.6 g) having the following physical data.

TLC: Rf 0.72 (chloroform:methanol=10:1); NMR(CDCl₃): δ 7.06(dd, J=7.8,7.6 Hz, 1H), 6.88(d, J=7.6 Hz, 1H), 6.70(d, J=7.8 Hz, 1H), 5.88(t, J=4.4Hz, 1H), 4.93(s, 1H), 3.68(s, 3H), 2.82–2.62(m, 4H), 2.58–2.49(m, 2H),2.26(m, 2H).

REFERENCE EXAMPLE 3 5-pivaloyloxy-1,2,3,4-tetrahydronaphthalen-1-one

To a pyridine (180 ml) solution of 5-hydroxy-1-tetralone (30.0 g),4-dimethylaminopyridine (1.13 g) was added, and pivaloyl chloride (25.0ml) was added thereto under ice-cooling, followed by stirring at roomtemperature overnight. The reaction mixture was ice-cooled, and aconcentrated hydrochloric acid was added thereto, followed by extractingwith ethyl acetate. The extract was washed with water and saturatedsaline in this order, dried with anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=9:1 to 5:1) to thereby obtain thetitle compound (45.4 g) having the following physical data.

TLC: Rf 0.42 (hexane :ethyl acetate=5:1); NMR(CDCl₃): δ 7.95(dd,J=7.8,1.4 Hz, 1H), 7.33(t, J=7.8 Hz, 1H), 7.19(dd, J=7.8, 1.4 Hz, 1H), 2.79(t,J=6.0 Hz, 2H), 2.65(dd, J=7.6, 6.0 Hz, 2H), 2.19–2.05(m, 2H), 1.40(s,9H).

REFERENCE EXAMPLE 42-(1-hydroxy-5-pivaloyloxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acidethyl ester

To an anhydrous benzene (60 ml) suspension of zinc (16.9 g), iodine(catalytic amount) was added, followed by refluxing under heating, andan anhydrous benzene (120 ml) solution of the compound (45.4 g) preparedin Reference Example 3 and bromoacetic acid ethyl ester (25.0 ml) wasadded dropwise thereto, followed by refluxing under heating overnight.The reaction mixture was cooled to room temperature. The reactionmixture was added to iced water, and a concentrated hydrochloric acidwas added thereto, followed by extracting with ethyl acetate. Theextract was washed with water and saturated saline in this order, driedwith anhydrous magnesium sulfate, and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=8:1to 5:1) to thereby obtain the title compound (33.5 g) having thefollowing physical data.

TLC: Rf 0.52 (hexane:ethyl acetate=85:15); NMR(CDCl₃): δ 7.42(dd, J=8.0,2.0 Hz, 1H), 7.17(t, J=8.0 Hz, 1H), 6.85(dd, J=8.0, 2.0 Hz, 1H), 4.16(q,J=7.0 Hz, 2H), 4.10–3.90(br, 1H), 2.80(d, J=14.0 Hz, 1H), 2.76(d, J=14.0Hz, 1H), 2.68–2.40(m, 2H), 2.12–1.44(m, 4H), 1.35(s, 9H), 1.24(t, J=7.0Hz, 3H).

REFERENCE EXAMPLE 5 2-(5-pivaloyloxy-3,4-dihydronaphthalen-1-yl)aceticacid ethyl ester

To a toluene (80 ml) solution of the compound (33.5 g) prepared inReference Example 4, p-toluenesulfonic acid monohydrate (1.52 g) wasadded, followed by refluxing under heating overnight. The reactionmixture was cooled to room temperature, diluted with ethyl acetate,washed with water, a saturated aqueous sodium hydrogen carbonatesolution, water and a saturated saline in this order, dried withanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=20:1 to 10:1)to thereby obtain the title compound (13.2 g) having the followingphysical data.

TLC: Rf 0.56 (hexane:ethyl acetate=3:1); NMR(CDCl₃): δ 7.18(t, J=8.0 Hz,1H), 7.08(dd, J=8.0, 1.0 Hz, 1H), 6.86(dd, J=8.0, 1.0 Hz, 1H), 6.01(t,J=4.5 Hz, 1H), 4.14(q, J=7.0 Hz, 2H), 3.44–3.40(m, 2H), 2.63(t, J=8.0Hz, 2H), 2.36–2.23(m, 2H), 1.38(s, 9H), 1.22(t, J=7.0 Hz, 3H).

REFERENCE EXAMPLE 6 2-(5-hydroxy-3,4-dihydronaphthalen-1-yl)acetic acidethyl ester

Under ice-cooling, to an ethanol (50 ml) solution of the compound (13.2g) prepared in Reference Example 5, an ethanol solution of sodiumethylate (20 ml, 2.6 M) was added dropwise, followed by stirring at roomtemperature for 3 hours. The reaction mixture was added to a mixture of2N hydrochloric acid and ice, followed by extracting with ethyl acetate.The extract was washed with a saturated saline, dried with anhydrousmagnesium sulfate, and concentrated. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1 to 2:1). Theobtained oil was subjected to crystallization by a mixture solvent ofhexane and ethyl acetate. Furthermore, the obtained crystal wassubjected to recrystallization by a mixture solvent of hexane and ethylacetate to thereby obtain the title compound (7.73 g) having thefollowing physical data.

TLC: Rf 0.34 (hexane:ethyl acetate=3:1); NMR(CDCl₃): δ 7.00(t, J=8.0 Hz,1H), 6.78(d, J=8.0, 1.0 Hz, 1H), 6.63(dd, J=8.0, 1.0 Hz, 1H), 5.98(t,J=4.5 Hz, 1H), 5.25(brs, 1H), 4.15(q, J=7.0 Hz, 2H), 3.44–3.41(m, 2H),2.74(t, J=8.0 Hz, 2H), 2.36–2.23(m, 2H), 1.23(t, J=7.0 Hz, 3H).

REFERENCE EXAMPLE 75-(5-methoxy-3,4-dihydronaphthalen-1(2H)ylidene)pentanoic acid

To an anhydrous tetrahydrofuran (200 ml) solution of(4-carboxybutyl)triphenylphosphonium bromide (25.0 g), potassiumt-butoxide (12.7 g) was added, followed by stirring at 30° C. for 1hour. To the reaction mixture, a tetrahydrofuran (20 ml) solution of5-methoxy-1-tetralone (5.0 g) was added, followed by stirring at roomtemperature overnight. The reaction mixture was added to a mixture ofsaturated aqueous ammonium chloride solution and ice, followed byextracting with ethyl acetate. The extract was concentrated to therebyobtain the crude title compound having the following physical data. Theobtained compound was used without purification in the subsequentreaction.

TLC: Rf 0.34 (hexane:ethyl acetate=2:1).

REFERENCE EXAMPLE 85-(5-methoxy-3,4-dihydronaphthalen-1(2H)ylidene)pentanoic acid methylester

To an anhydrous dimethylformamide (40 ml) solution of the compoundprepared in Reference Example 7, methyl iodide (5.3 ml) and potassiumcarbonate (17.6 g) were added, followed by stirring at room temperatureovernight. The reaction mixture was added to iced water, followed byextracting with ethyl acetate. The extract was washed with a saturatedsaline, dried with anhydrous magnesium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=5:1) to thereby obtain the title compound (6.80 g) having thefollowing physical data.

TLC: Rf 0.72 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.18(dd, J=7.6,1.2 Hz, 1H), 7.10(t, J=7.6 Hz, 1H), 6.70(dd, J=7.6, 1.2 Hz, 1H),5.96(brt, J=7.2 Hz, 1H), 3.81(s, 3H), 3.66(s, 3H), 2.71(t, J=6.4 Hz,2H), 2.48–2.18(m, 6H), 1.89–1.71(m, 4H).

REFERENCE EXAMPLE 9 5-(5-hydroxy-3,4-dihydronaphthalen-1-yl)pentanoicacid

The mixture of the compound (6.83 g) prepared in Reference Example 8 andpyridine hydrochloric acid (39 g) was stirred at 180° C. for 2 hours.The reaction mixture was cooled to room temperature, and water was addedthereto, followed by extracting with ethyl acetate. The extract waswashed with 2N hydrochloric acid and saturated saline in this order,dried with anhydrous magnesium sulfate, and concentrated to therebyobtain the crude title compound having the following physical data. Theobtained compound was used without purification in the subsequentreaction

TLC: Rf 0.12 (hexane:ethyl acetate=2:1).

REFERENCE EXAMPLE 10 5-(5-hydroxy-3,4-dihydronaphthalen-1-yl)pentanoicacid methyl ester

Thionyl chloride (1.9 ml) was added to methanol (25 ml) at −30° C.,followed by stirring at −20° C. for 15 minutes. To the reactionsolution, the methanol (10 ml) solution of the compound prepared inReference Example 9 was added, followed by stirring at room temperaturefor 30 minutes. The reaction mixture was concentrated. The residue wasdiluted with ethyl acetate. The diluted solution was washed with asaturated aqueous sodium hydrogen carbonate solution, water andsaturated saline in this order, dried with anhydrous magnesium sulfate,and concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to thereby obtain the titlecompound (4.91 g) having the following physical data

TLC: Rf 0.48 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.08(t, J=7.8 Hz,1H), 6.86(brd, J=7.8 Hz, 1H), 6.68(dd, J=7.8, 1.0 Hz, 1H), 5.85(t, J=4.4Hz, 1H), 4.96(brs, 1H), 3.66(s, 3H), 2.70(t, J=8.0 Hz, 2H), 2.49–2.17(m,6H), 1.89–1.45(m, 4H).

REFERENCE EXAMPLE 11N′-((1E)-5-hydroxy-3,4-dihydronaphthalen-1(2H)ylidene)-2,4,6-triisopropylbenzenesulfonohydrazide

To a methanol (250 ml) solution of2,4,6-triisopropylbenzenesulfonylhydrazide (36.8 g) and5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-one (20.0 g), a concentratedhydrochloric acid (4.3 ml) was added at room temperature, followed bystirring at 40° C. for 2 hours. Under ice-cooling, the reaction mixturewas stirred for 1 hour. The deposited crystal was separated. Theseparation was washed with cold methanol, dried under reduced pressureto thereby obtain the title compound (49.2 g) having the followingphysical data.

TLC: Rf 0.28 (hexane:ethyl acetate=3:1); NMR(CDCl₃): δ 7.57(br, 1H),7.56(d, J=8.1 Hz, 1H), 7.16(s, 2H), 6.99(t, J=8.1 Hz, 1H), 6.71(d, J=8.1Hz, 1H), 4.37 –4.24(m, 2H), 2.88(m, 1H), 2.69(t, J=6.0 Hz, 2H), 2.43(t,J=6.6 Hz, 2H), 1.96–1.85(m, 2H), 1.30(d, J=6.9 Hz, 12H), 1.23(d, J=6.9Hz, 6H).

REFERENCE EXAMPLE 12 5-hydroxy-3,4-dihydronaphthalen-1-ylmethanol

To an anhydrous tetrahydrofuran (510 ml) solution of the compound (49.2g) prepared in Reference Example 11, n-butyl lithium (221 ml, 1.56 M inhexane) was added at −78° C., followed by stirring at −78° C. for 30minutes. The reaction mixture was heated up to 0° C., followed bystirring at 0° C. for 30 minutes. Under ice-cooling, paraformaldehyde(11.7 g) was added to the reaction mixture, followed by heating up toroom temperature, and the reaction mixture was stirred for 1 hour. Underice-cooling, a saturated aqueous ammonium chloride solution was added tothe reaction mixture for liquid separation. The aqueous layer wasextracted with ethyl acetate. The combined organic layer was washed witha saturated saline, dried with anhydrous sodium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1 to 1:1) to thereby obtain thetitle compound (15.7 g) having the following physical data.

TLC: Rf 0.28 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 9.17(brs, 1H),6.94(t, J=8.1 Hz, 1H), 6.74(d, J=8.1 Hz, 1H), 6.68(dd, J=8.1, 1.2 Hz,1H), 6.01(t, J=4.8 Hz, 1H), 4.50(brs, 1H), 4.25(d, J=1.2 Hz, 2H),2.60(t, J=7.8 Hz, 2H), 2.22–2.09(m, 2H).

REFERENCE EXAMPLE 13 5-methoxymethoxy-3,4-dihydronaphthalen-1-ylmethanol

Under ice-cooling, to an anhydrous tetrahydrofuran (135 ml) solution ofthe compound (15.7 g) prepared in Reference Example 12, sodium hydride(3.75 g, 63.1%) was added, followed by stirring at room temperature for30 minutes. To the reaction mixture, chloromethyl methyl ether (7.41 ml)was added dropwise under ice-cooling, followed by stirring at roomtemperature for 13 hours. To the reaction mixture, iced water and asaturated aqueous ammonium chloride solution were added, followed byextracting with ethyl acetate. The extract was washed with water andsaturated saline in this order, dried with anhydrous sodium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1 to 2:1) to thereby obtain thetitle compound (15.1 g) having the following physical data.

TLC: Rf 0.38 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.16(t, J=7.8 Hz,1H), 7.05(d, J=7.8 Hz, 1H), 7.00(d, J=7.8 Hz, 1H), 6.14(t, J=4.5 Hz,1H), 5.20(s, 2H), 4.51(brs, 2H), 3.49(s, 3H), 2.82(t, j=8.1 Hz, 2H),2.30(td, j=8.1, 4.5 Hz, 2H), 1.46(brs, 1H).

REFERENCE EXAMPLE 141-bromomethyl-5-methoxymethoxy-3,4-dihydronaphthalene

To a methylene chloride (110 ml) solution of the compound (7.53 g)prepared in Reference Example 13 and triphenylphosphine (9.59 g),tetrabromomethane (12.1 g) was added under ice-cooling, followed bystirring under ice-cooling for 40 minutes. The reaction mixture wasconcentrated. To the residue, a mixed solvent of diethyl ether andhexane (5:1) was added for excluding triphenylphosphine oxide. Theobtained crude product was purified by silica gel column chromatography(hexane: ethyl acetate=20:1 to 10:1) to thereby obtain the titlecompound (6.32 g) having the following physical data.

TLC: Rf 0.76 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.20(t, J=8.1 Hz,1H), 7.12(d, J=8.1 Hz, 1H), 7.03(d, J=8.1 Hz, 1H), 6.30(t, J=4.8 Hz,1H), 5.20(s, 2H), 4.36(s, 2H), 3.49(s, 3H), 2.83(t, J=8.7 Hz, 2H),2.31(td, J=8.7, 4.8 Hz, 2H).

REFERENCE EXAMPLE 152,2-dimethyl-3-(5-methoxymethoxy-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

Under ice-cooling, to an anhydrous tetrahydrofuran (30 ml) solution of2-methylpropanoic acid methyl ester (5.11 ml), lithium diisopropylamide(22.3 ml) was added dropwise, followed by stirring at 30° C. for 30minutes. Under ice-cooling, to the reaction mixture, an anhydroustetrahydrofuran (20 ml) solution of the compound (6.32 g) prepared inReference Example 14 was added dropwise, followed by stirring at roomtemperature for 2 hours. To the reaction mixture, a saturated aqueousammonium chloride solution was added, followed by extracting with ethylacetate. The extract was washed with saturated saline, dried withanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=8:1 to 6:1) tothereby obtain the title compound (7.02 g) having the following physicaldata.

TLC: Rf 0.55 (hexane:ethyl acetate=5:1); NMR(CDCl₃): δ 7.10(t, J=8.1 Hz,1H), 6.97(d, J=8.1 Hz, 1H), 6.94(d, J=8.1 Hz, 1H), 5.85(t, J=4.5 Hz,1H), 3.49(s, 3H), 3.47(s, 3H), 2.74(t, J=7.8 Hz, 2H), 2.72(s, 2H),2.17(td, J=7.8, 4.5 Hz, 2H), 1.15(s, 6H).

REFERENCE EXAMPLE 162,2-dimethyl-3-(5-hydroxy-3,4-dihydronaphthalen-1-yl)propanoic acidmethyl ester

To a methanol (110 ml) solution of the compound (6.78 g) prepared inReference Example 15, 4N hydrogen chloride-dioxane solution (8.4 ml) wasadded, followed by stirring at room temperature for 15 hours. Thereaction mixture was concentrated. The residue was extracted with ethylacetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated saline in this order, dried withanhydrous sodium sulfate, and concentrated to thereby obtain the titlecompound (5.78 g) having the following physical data.

TLC: Rf 0.30 (hexane:ethyl acetate=5:1); NMR(CDCl₃): δ 7.03(t, J=8.1 Hz,1H), 6.89(d, J=8.1 Hz, 1H), 6.65(dd, J=1.2, 8.1 Hz, 1H), 5.85(t, J=4.5Hz, 1H), 4.71(s, 1H), 3.46(s, 3H), 2.71(d, J=1.2 Hz, 2H), 2.67(t, J=8.1Hz, 2H), 2.20(td, J=8.1, 4.5 Hz, 2H), 1.56(s, 6H).

REFERENCE EXAMPLE 171-cyclopropylidene-5-methoxy-1,2,3,4-tetrahydronaphthalene

Under ice-cooling, to an anhydrous tetrahydrofuran (200 ml) solution of(3-bromopropyl)triphenylphosphinium bromide (19.8 g), potassiumt-butoxide (9.58 g) was added, followed by stirring at room temperaturefor 1.5 hours. To the reaction mixture, 5-methoxy-1-tetralone (5.0 g)was added, followed by stirring at room temperature for 5 hours. Thereaction mixture was poured into a saturated aqueous ammonium chloridesolution. The aqueous layer was extracted with ethyl acetate. Thecombined organic layer was washed with saturated saline, dried withanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=10:1) tothereby obtain the title compound (5.66 g) having the following physicaldata.

TLC: Rf 0.86 (hexane:ethyl acetate=10:1); NMR(CDCl₃): δ 7.56(d, J=7.8Hz, 1H), 7.13(t, J=7.8 Hz, 1H), 6.70(d, J=7.8 Hz, 1H), 3.83(s, 3H),2.76(t, J=6.4 Hz, 2H), 2.66–2.56(m, 2H), 1.94–1.80(m, 2H), 1.51–1.40(m,2H), 1.12–1.02(m, 2H).

REFERENCE EXAMPLE 18 1-(3-bromopropyl)-5-methoxy-3,4-dihydronaphthalene

To a acetic acid (60 ml) solution of the compound (5.00 g) prepared inReference Example 17, 47% hydrogen bromide aqueous solution (20 ml) wasadded, followed by stirring at room temperature for 2 hours. To thereaction mixture, iced water was added, followed by extracting withethyl acetate. The extract was washed with saturated saline, dried withanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=10:1) tothereby obtain the title compound (7.05 g) having the following physicaldata.

TLC: Rf 0.69 (hexane:ethyl acetate=10:1); NMR(CDCl₃): δ 7.16(t, J=7.8Hz, 1H), 6.90(d, J=7.8 Hz, 1H), 6.79(d, J=7.8 Hz, 1H), 5.92(t, J=4.6 Hz,1H), 3.83(s, 3H), 3.44(t, J=6.6 Hz, 2H), 2.74(t, J=7.6 Hz, 2H),2.65–2.55(m, 2H), 2.28–2.15(m, 2H), 2.13–1.98(m, 2H).

REFERENCE EXAMPLE 192,2-dimethyl-5-(5-methoxy-3,4-dihydronaphthalen-1-yl)pentanoic acidmethyl ester

Under ice-cooling, to an anhydrous tetrahydrofuran (15 ml) solution of2-methylpropanoic acid methyl ester (3.30 g), lithium diisopropylamide(16.5 ml, 2.0 M) was added, followed by stirring at 30° C. for 30minutes. The reaction mixture was cooled to room temperature, and ananhydrous tetrahydrofuran (5 ml) solution of the compound (3.00 g)prepared in Reference Example 18 was added thereto, followed by stirringat room temperature for 3 hours. The reaction mixture was poured into asaturated aqueous ammonium chloride solution, followed by extractingwith ethyl acetate. The extract was washed with saturated saline, driedwith anhydrous magnesium sulfate, and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=100:1to 20:1) to thereby obtain the crude title compound (3.68 g) having thefollowing physical data. The obtained compound was used withoutpurification in the subsequent reaction.

TLC: Rf 0.84 (hexane:ethyl acetate=2:1).

REFERENCE EXAMPLE 202,2-dimethyl-5-(5-hydroxy-3,4-dihydronaphthalen-1-yl)pentanoic acid

The mixture of the compound (3.68 g) prepared in Reference Example 19and pyridine hydrochloric acid (17 g) was stirred at 180° C. overnight.The reaction mixture was cooled to room temperature, and water was addedthereto, followed by extracting with ethyl acetate. The extract waswashed with saturated saline, dried with anhydrous magnesium sulfate,and concentrated to thereby obtain the crude title compound having thefollowing physical data. The obtained compound was used withoutpurification in the subsequent reaction.

TLC: Rf 0.30 (hexane:ethyl acetate=2:1).

REFERENCE EXAMPLE 212,2-dimethyl-5-(5-hydroxy-3,4-dihydronaphthalen-1-yl)pentanoic acidmethyl ester

Thionyl chloride (0.86 ml) was added to cold methanol (11 ml), followedby stirring at −20° C. for 15 minutes. To the reaction solution, amethanol (5 ml) solution of the compound prepared in Reference Example20 was added, followed by stirring at room temperature for 1 hour. Thereaction mixture was concentrated. The residue was diluted with ethylacetate. The diluted solution was washed with a saturated aqueous sodiumhydrogen carbonate solution and saturated saline in this order, driedwith anhydrous magnesium sulfate, and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=8:1)to thereby obtain the title compound (2.02 g) having the followingphysical data.

TLC: Rf 0.66 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.05(t, J=8.0 Hz,1H), 6.84(d, J=8.0 Hz, 1H), 6.68(dd, J=8.0, 1.0 Hz, 1H), 5.84(t, J=4.8Hz, 1H), 5.01(brs, 1H), 3.60(s, 3H), 2.70(t, J=8.0 Hz, 2H), 2.44–2.32(m,2H), 2.30–2.17(m, 2H), 1.75–1.34(m, 4H), 1.15(s, 6H).

REFERENCE EXAMPLE 222-benzyloxy-3-(5-methoxymethoxy-3,4-dihydronaphthalen-1-yl)propanoicacid

To a tetrahydrofuran (7 ml) solution of 2-benzyloxyacetic acid (0.30ml), lithium diisopropylamide (2.4 ml) was added dropwise at −78° C.under argon atmosphere, followed by stirring at 0° C. for 10 minutes.The above obtained solution was added to a tetrahydrofuran (3 ml)solution of the compound (600 mg) prepared in Reference Example 14 at−78° C., followed by stirring at room temperature for 12 hours. Thereaction mixture was poured into a saturated aqueous ammonium chloridesolution for liquid separation. The aqueous layer was extracted withethyl acetate. The combined organic layer was washed with saturatedsaline, dried with anhydrous magnesium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography(chloroform:methanol=50:1) to thereby obtain the title compound (99 mg)having the following physical data.

TLC: Rf 0.33 (hexane:ethyl acetate=4:1).

REFERENCE EXAMPLE 232-benzyloxy-3-(5-hydroxy-3,4-dihydronaphthalen-1-yl)propanoic acidmethyl ester

To a methanol (4 ml) solution of the compound (99 mg) prepared inReference Example 22, 4N hydrogen chloride-dioxane solution (0.1 ml) wasadded, followed by stirring at room temperature for 15 hours. Thereaction mixture was concentrated to thereby obtain the crude titlecompound having the following physical data. The obtained compound wasused without purification in the subsequent reaction.

TLC: Rf 0.48 (hexane:ethyl acetate=2:1).

REFERENCE EXAMPLE 24 3-methoxycarbonyl-2-(4-methylbenzoylamino)propanoicacid

Aspartic acid β-methyl ester hydrochloride (184 g) was dissolved inwater (1.3 L), and sodium hydrogen carbonate (277 g) was added thereto,and tetrahydrofuran (450 ml) and a tetrahydrofuran (50 ml) solution of4-methylbenzoyl chloride (146 ml) was added dropwise thereto, followedby stirring at room temperature for 15 hours. The reaction mixture waswashed with ethyl acetate. The aqueous layer was neutralized with 2Nhydrochloric acid to pH 2 to 3, and extracted with ethyl acetate. Theextract was washed with saturated saline, dried with anhydrous magnesiumsulfate, and concentrated to thereby obtain the crude title compound(255 g) having the following physical data. The obtained compound wasused without purification in the subsequent reaction.

TLC: Rf 0.28 (chloroform:methanol=5:1); NMR(CDCl₃): δ 7.71(d, J=8.1 Hz,2H), 7.34(d, J=7.8 Hz, 1H), 7.24(d, J=8.1 Hz, 2H), 5.08(ddd, J=7.5, 4.5,4.5 Hz, 1H), 3.73(s, 3H), 3.18(dd, J=17.1, 4.5 Hz, 1H), 3.00(dd, J=17.1,4.5 Hz, 1H), 2.40(s, 3H).

REFERENCE EXAMPLE 25 3-acetyl-3-(4-methylbenzoylamino)propanoic acidmethyl ester

To a pyridine (480 ml) solution of the compound (255 g) prepared inReference Example 24, acetic anhydride (453 ml) and4-dimethylaminopyridine (3.52 g) were added, followed by stirring at 90°C. for 1 hour. The reaction mixture was cooled to room temperature, andconcentrated. The residue was poured into iced water, followed byextracting with ethyl acetate. The extract was washed with water, 2Nhydrochloric acid and saturated saline in this order, dried withanhydrous magnesium sulfate, and concentrated to thereby obtain thecrude title compound having the following physical data.

TLC: Rf 0.23 (hexane:ethyl acetate=2:1).

REFERENCE EXAMPLE 26 2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)aceticacid methyl ester

To a acetic anhydride (450 ml) solution of the compound prepared inReference Example 25, concentrated sulfuric acid (86 ml) was added,followed by stirring at 90° C. for 1 hour. The reaction mixture wascooled to room temperature, and poured into ice. The aqueous layer wasneutralized with 5N aqueous sodium hydroxide solution, and extractedwith ethyl acetate. The extract was washed with 1N aqueous sodiumhydroxide solution, water and saturated saline in this order, dried withanhydrous magnesium sulfate, and concentrated. The obtained oil wasallowed to stand overnight. The obtained solid was washed with hexane,and filtered off by aspiration to thereby obtain the title compound (183g) having the following physical data.

TLC: Rf 0.61 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.87(d, J=8.1 Hz,2H), 7.23(d, J=8.1 Hz, 2H), 3.73(s, 3H), 3.57(s, 2H), 2.38(s, 3H),2.35(s, 3H).

REFERENCE EXAMPLE 27 2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethanol

Under ice-cooling, lithium aluminum hydride (18.6 g) was suspended inanhydrous tetrahydrofuran (250 ml), and an anhydrous tetrahydrofuran(250 ml) of the compound (120 g) prepared in Reference Example 26 wasadded dropwise thereto, followed by stirring for 30 minutes underice-cooling. To the reaction mixture, a saturated aqueous sodium sulfatesolution was added dropwise for liquid separation. The organic layer wasdried with anhydrous magnesium sulfate, and filtered with celite. Thefiltrate was concentrated. The residue was allowed to stand overnight.The obtained crystal was washed with a mixed solvent of hexane and ethylacetate (10:1) to thereby obtain the title compound (80.0 g) having thefollowing physical data.

TLC Rf 0.18 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.86(m, 2H),7.23(m, 2H), 3.92(br, 2H), 2.71(t, J=6.0 Hz, 2H), 2.39(s, 3H), 2.32(s,3H).

EXAMPLE 13-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

To a methylene chloride (15 ml) solution of the compound (600 mg)prepared in Reference Example 2, the compound (617 mg) prepared inReference Example 27, triphenylphosphine (1.02 g) and1,1′-(azodicarbonyl)dipiperidine (978 mg) were added, followed bystirring at room temperature for 3 hours. The reaction mixture wasdiluted with diethyl ether, and filtered with celite. The filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=9:1 to 7:1 to 5:1 to7:2) to thereby obtain the compound of the present invention (1.00 g)having the following physical data.

TLC: Rf 0.59 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.86(d, J=8.1 Hz,2H), 7.23(d, J=8.1 Hz, 2H), 7.13(dd, J=8.0, 8.0 Hz, 1H), 6.94–6.74(m,2H), 5.87(dd, J=4.6, 4.6 Hz, 1H), 4.25(t, J=6.6 Hz, 2H), 3.67(s, 3H),2.99(t, J=6.6 Hz, 2H), 2.85–2.63(m, 4H), 2.60–2.45(m, 2H), 2.39(s, 3H),2.36(s, 3H), 2.30–2.10(m, 2H).

EXAMPLE 1(1) TO EXAMPLE 1(46)

The following compounds of the present invention were obtained in thesame manner as in Example 2 using the compound prepared in ReferenceExample 2 or a corresponding phenol derivative instead thereof(Reference Example 6, Reference Example 10, Reference Example 16,Reference Example 21, Reference Example 23 and2-(5-hydroxy-3,4-dihydronaphthalen-1-yl)acetic acid ethyl ester), andthe compound prepared in Reference Example 27 or a corresponding ethanolderivative instead thereof.

EXAMPLE 1(1)3-(5-(2-(2-phenyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.59 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 8.02–7.94(m, 2H),7.47–7.37(m, 3H), 7.13(t, J=8.0 Hz, 1H), 6.89(d, J=8.0 Hz, 1H), 6.80(d,J=8.0 Hz, 1H), 5.87(brt, J=4.5 Hz, 1H), 4.25(t, J=6.6 Hz, 2H), 3.67(s,3H), 2.99(t, J=6.6 Hz, 2H), 2.82–2.65(m, 4H), 2.58–2.47(m, 2H), 2.37(s,3H), 2.27–2.11(m, 2H).

EXAMPLE 1(2)3-(5-(2-(2-(6-dimethylaminopyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.16 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 8.74(dd, J=2.4,0.8 Hz, 1H), 7.99(dd, J=9.0, 2.4 Hz, 1H), 7.13(d, J=8.0 Hz, 1H), 6.88(d,J=8.0 Hz, 1H), 6.81(d, J=8.0 Hz, 1H), 6.52(dd, J=9.0, 0.8 Hz, 1H),5.87(brt, J=4.6 Hz, 1H), 4.24(t, J=6.8 Hz, 2H), 3.67(s, 3H), 3.14(s,6H), 2.96(t, J=6.8 Hz, 2H), 2.82–2.65(m, 4H), 2.57–2.47(m, 2H), 2.34(s,3H), 2.27–2.11(m, 2H).

EXAMPLE 1(3)3-(5-(2-(2-(1,3-dioxaindan-5-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.49 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.51(dd, J=8.2,1.6 Hz, 1H), 7.43(d, J=1.6 Hz, 1H), 7.13(dd, J=8.0, 8.0 Hz, 1H),6.94–6.76(m, 3H), 6.01(s, 2H), 5.87(dd, J=4.5, 4.5 Hz, 1H), 4.24(t,J=6.6 Hz, 2H), 3.67(s, 3H), 2.96(t, J=6.6 Hz, 2H), 2.84–2.62(m, 4H),2.60–2.45(m, 2H), 2.34(s, 3H), 2.26–2.10(m, 2H).

EXAMPLE 1(4)3-(5-(2-(2-(4-t-butylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.61 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.89(d, J=8.6 Hz,2H), 7.44(d, J=8.6 Hz, 2H), 7.12(dd, J=8.2, 8.0 Hz, 1H), 6.88(d, J=8.0Hz, 1H), 6.80(d, J=8.0 Hz, 1H), 5.87(t, J=6.6 Hz, 1H), 4.24(t, J=6.6 Hz,2H), 3.67(s, 3H), 2.98(t, J=6.6 Hz, 2H), 2.82–2.63(m, 4H), 2.58–2.47(m,2H), 2.37(s, 3H), 2.26–2.10(m, 2H), 1.34(s, 9H).

EXAMPLE 1(5)3-(5-(2-(2-(6-(morpholin-4-yl)pyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.75 (chloroform:methanol=10:1); NMR(CDCl₃): δ 8.76(d, J=1.8 Hz,1H), 8.04(dd, J=8.8, 1.8 Hz, 1H), 7.13(dd, J=8.0, 7.8 Hz, 1H), 6.89(d,J=7.8 Hz, 1H), 6.80(d, J=8.0 Hz, 1H), 6.64(d, J=8.8 Hz, 1H), 5.87(m,1H), 4.23(t, J=6.4 Hz, 2H), 3.82(m, 4H), 3.59(m, 4H), 2.96(t, J=6.4 Hz,2H), 2.83–2.63(m, 4H), 2.57–2.48(m, 2H), 2.08(m, 2H).

EXAMPLE 1(6)3-(5-(2-(2-(4-dimethylaminophenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.37 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.80(d, J=9 Hz,2H), 7.15(m, 1H), 6.90–6.70(m, 4H), 5.90(t, J=4 Hz, 1H), 4.25(t, J=7 Hz,2H), 3.70(s, 3H), 3.00(s, 6H), 2.95(t, J=7 Hz, 2H), 2.80–2.50(m, 6H),2.35(s, 3H), 2.20(m, 2H).

EXAMPLE 1(7)3-(5-(2-(2-isopropyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.57 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.15(dd, J=7.5,7.5 Hz, 1H), 6.90(d, J=7.5 Hz, 1H), 6.80(d, J=7.5 Hz, 1H), 5.90(t, J=4Hz, 1H), 4.20–4.10(m, 4H), 3.00(m, 1H), 2.90(t, J=6 Hz, 2H), 2.75(m,2H), 2.65(t, J=8.5 Hz, 2H), 2.55(t, J=8.5 Hz, 2H), 2.20(s, 3H), 2.20(m,2H), 1.35–1.20(m, 9H).

EXAMPLE 1(8)3-(5-(2-(2-(4-trifluoromethylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.73 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 8.10(d, J=8 Hz,2H), 7.70(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.95–6.80(m, 2H),5.85(m, 1H), 4.25(t, J=6 Hz, 2H), 4.15(q, J=7 Hz, 2H), 3.00(t, J=6 Hz,2H), 2.80–2.65(m, 4H), 2.50(m, 2H), 2.40(s, 3H), 2.20(m,2H), 1.25(t, J=7Hz, 3H).

EXAMPLE 1(9)3-(5-(2-(2-(4-trifluoromethyloxyphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.74 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 8.00(d, J=9 Hz,2H), 7.25(d, J=9 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.90(d, J=8 Hz, 1H),6.80(d, J=8 Hz, 1H), 5.85(m, 1H), 4.25(t, J=6 Hz, 2H), 4.15(q, J=7 Hz,2H), 3.00(t, J=6 Hz, 2H), 2.80–2.60(m, 4H), 2.50(m, 2H), 2.40(s, 3H),2.20(m,2H), 1.25(t, J=7 Hz, 3H).

EXAMPLE 1(10)3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.58 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.85(d, J=8 Hz,2H), 7.25(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.90(d, J=8 Hz, 1H),6.80(d, J=8 Hz, 1H), 5.85(m, 1H), 4.25(t, J=7 Hz, 2H), 4.15(q, J=10 Hz,2H), 3.00(t, J=7 Hz, 2H), 2.80–2.65(m, 4H), 2.50(m, 2H), 2.40(s, 3H),2.20(m, 2H), 1.25(t, J=10 Hz, 3H).

EXAMPLE 1 (11)3-(5-(2-(2-(4-chlorophenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.64 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.95(d, J=8 Hz,2H), 7.40(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.90(d, J=8 Hz, 1H),6.80(d, J=8 Hz, 1H), 5.85(t, J=4 Hz, 1H), 4.20(t, J=6 Hz, 2H), 4.15(q,J=7 Hz, 2H), 3.00(t, J=6 Hz, 2H), 2.80–2.65(m, 4H), 2.50(m, 2H), 2.40(s,3H), 2.20(m,2H), 1.25(t, J=7 Hz, 3H).

EXAMPLE 1(12)3-(5-(2-(2-(4-methylthiophenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.50 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.85(d, J=8 Hz,2H), 7.30(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.90(d, J=8 Hz, 1H),6.80(d, J=8 Hz, 1H), 5.85(t, J=4 Hz, 1H), 4.25(t, J=7 Hz, 2H), 4.15(q,J=7 Hz, 2H), 3.00(t, J=7 Hz, 2H), 2.80–2.65(m, 4H), 2.50(s, 3H), 2.50(m,2H), 2.35(s, 3H), 2.10(m,2H), 1.25(t, J=7 Hz, 3H).

EXAMPLE 1(13)3-(5-(2-(2-(4-isopropylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.65 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.90(d, J=8 Hz,2H), 7.25(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.90(d, J=8 Hz, 1H),6.80(d, J=8 Hz, 1H), 5.85(t, J=4 Hz, 1H), 4.25(t, J=6 Hz, 2H), 4.15(q,J=7 Hz, 2H), 3.00–2.90(m, 3H), 2.80–2.65(m, 4H), 2.50(m, 2H), 2.35(s,3H), 2.20(m,2H), 1.20(d, J=8 Hz, 6H), 1.20(t, J=7 Hz, 3H).

EXAMPLE 1(14)3-(5-(2-(2-(4-propylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.65 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.80(d, J=8 Hz,2H), 7.25(d, J=8 Hz, 2H), 7.10(m, 1H), 6.90(m, 1H), 6.75(m, 1H), 5.85(m,1H), 4.25(t, J=6 Hz, 2H), 4.15(q, J=7 Hz, 2H), 3.00(t, J=6 Hz, 2H),2.80–2.60(m, 8H), 2.55(m, 2H), 2.35(s, 3H), 2.20(m, 2H), 1.25(t, J=7 Hz,3H), 0.95(t, J=8 Hz, 3H).

EXAMPLE 1 (15)3-(5-(2-(2-(2,2-difluoro-1,3-dioxaindan-5-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.61 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.75(m, 1H),7.70(m, 1H), 7.15–7.05(m, 2H), 6.90(d, J=8 Hz, 1H), 6.80(d, J=8 Hz, 1H),5.85(t, J=4 Hz, 1H), 4.25(t, J=7 Hz, 2H), 4.15(q, J=7 Hz, 2H), 3.00(t,J=7 Hz, 2H), 2.80–2.65(m, 4H), 2.55(m, 2H), 2.35(s, 3H), 2.20(m,2H),1.25(t, J=7 Hz, 3H).

EXAMPLE 1(16)3-(5-(2-(2-(6-diethylaminopyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.32 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 8.71(d, J=2.4 Hz,1H), 7.94(dd, J=9.0, 2.4 Hz, 1H), 7.13(dd, J=7.8, 7.8 Hz, 1H), 6.89(d,J=7.8 Hz, 1H), 6.80(d, J=7.8 Hz, 1H), 6.47(d, J=9.0 Hz, 1H), 5.87(t,J=4.5 Hz, 1H), 4.23(t, J=6.6 Hz, 2H), 4.13(q, J=7.2 Hz, 2H), 3.55(q,J=7.2 Hz, 4H), 2.96(t, J=6.6 Hz, 2H), 2.82–2.62(m, 4H), 2.58–2.44(m,2H), 2.33(s, 3H), 2.26–2.10(m, 2H), 1.34–1.12(m, 9H).

EXAMPLE 1(17)3-(5-(2-(2-(piperidin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.63 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.12(t, J=7.8 Hz,1H), 6.88(d, J=7.8 Hz, 1H), 6.79(d, J=7.8 Hz, 1H), 5.87(t, J=4.8 Hz,1H), 4.21(t, J=6.9 Hz, 2H), 4.13(q, J=7.2 Hz, 2H), 3.36(t, J=4.8 Hz,4H), 2.95(t, J=6.9 Hz, 2H), 2.76(t, J=7.2 Hz, 2H), 2.70(t, J=8.7 Hz,2H), 2.51(t, J=8.7 Hz, 2H), 2.25(s, 3H), 2.23–2.14(m, 2H), 1.70–1.53(m,6H), 1.25(t, J=7.2 Hz, 3H).

EXAMPLE 1(18)3-(5-(2-(2-(4-methylpiperazin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.47 (chloroform:methanol=9:1); NMR(CDCl₃): δ 7.13(t, J=7.8 Hz,1H), 6.88(d, J=7.8 Hz, 1H), 6.79(d, J=7.8 Hz, 1H), 5.87(t, J=4.5 Hz,1H), 4.21(t, J=6.9 Hz, 2H), 4.13(q, J=7.2 Hz, 2H), 3.41(t, J=5.1 Hz,4H), 2.96(t, J=6.9 Hz, 2H), 2.76(t, J=8.1 Hz, 2H), 2.69(t, J=8.4 Hz,2H), 2.55–2.45(m, 6H), 2.33(s, 3H), 2.26(s, 3H), 2.23–2.13(m, 2H),1.25(t, J=7.2 Hz, 3H).

EXAMPLE 1(19)3-(5-(2-(2-(morpholin-4-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.36 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.13(t, J=8.1 Hz,1H), 6.89(d, J=8.1 Hz, 1H), 6.79(d, J=8.1 Hz, 1H), 5.87(t, J=4.8 Hz,1H), 4.21(t, J=6.6 Hz, 2H), 4.13(q, J=7.2 Hz, 2H), 3.79(t, J=4.8 Hz,4H), 3.37(t, J=4.8 Hz, 4H), 2.96(t, J=6.6 Hz, 2H), 2.76(t, J=7.8 Hz,2H), 2.69(t, J=7.8 Hz, 2H), 2.51(t, J=7.8 Hz, 2H), 2.27(s, 3H),2.24–2.14(m, 2H), 1.25(t, J=7.2 Hz, 3H).

EXAMPLE 1(20)3-(5-(2-(2-(thiomorpholin-4-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.62 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.13(t, J=7.8 Hz,1H), 6.89(d, J=7.8 Hz, 1H), 6.79(d, J=7.8 Hz, 1H), 5.87(t, J=4.5 Hz,1H), 4.20(t, J=6.6 Hz, 2H), 4.13(q, J=7.2 Hz, 2H), 3.77–3.70(m, 4H),2.94(t, J=6.6 Hz, 2H), 2.80–2.64(m, 8H), 2.50(t, J=7.8 Hz, 2H), 2.25(s,3H), 2.23–2.13(m, 2H), 1.25(t, J=7.2 Hz, 3H).

EXAMPLE 1(21)3-(5-(2-(2-(6-methylpyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.47 (chloroform:methanol=19:1); NMR(CDCl₃): δ 9.07(d, J=1.8 Hz,1H), 8.12(dd, J=8.1, 1.8 Hz, 1H), 7.21(d, J=8.1 Hz, 1H), 7.14(t, J=7.8Hz, 1H), 6.89(d, J=7.8 Hz, 1H), 6.80(d, J=7.8 Hz, 1H), 5.87(t, J=4.2 Hz,1H), 4.25(t, J=6.6 Hz, 2H), 4.13(q, J=7.2 Hz, 2H), 2.99(t, J=6.6 Hz,2H), 2.75(t, J=9.0 Hz, 2H), 2.69(t, J=8.4 Hz, 2H), 2.60(s, 3H), 2.50(t,J=8.4 Hz, 2H), 2.38(s, 3H), 2.24–2.14(m, 2H), 1.24(t, J=7.2 Hz, 3H).

EXAMPLE 1(22)3-(5-(2-(2-(1,5-dimethylpyrazol-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.56 (chloroform:methanol=19:1); NMR(CDCl₃): δ 7.12(t, J=8.1 Hz,1H), 6.88(d, J=8.1 Hz, 1H), 6.79(d, J=8.1 Hz, 1H), 6.51(s, 1H), 5.85(m,1H), 4.24(t, J=6.6 Hz, 2H), 4.13(q, J=7.2 Hz, 2H), 3.85(s, 3H), 2.97(t,J=6.6 Hz, 2H), 2.75(t, J=7.5 Hz, 2H), 2.68(t, J=8.4 Hz, 2H), 2.50(t,J=8.4 Hz, 2H), 2.35(s, 3H), 2.31(s, 3H), 2.23–2.13(m, 2H), 1.25(t, J=7.2Hz, 3H).

EXAMPLE 1(23)3-(5-(2-(2-(4-methylpiperidin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.63 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.12(t, J=7.8 Hz,1H), 6.88(d, J=7.8 Hz, 1H), 6.79(d, J=7.8 Hz, 1H), 5.90–5.84(m, 1H),4.21(t, J=6.9 Hz, 2H), 4.14(q, J=7.2 Hz, 2H), 3.90–3.72(m, 2H), 2.95(t,J=6.9 Hz, 2H), 2.94–2.81(m, 2H), 2.80–2.65(m, 4H), 2.54–2.47(m, 2H),2.24(s, 3H), 2.24–2.14(m, 2H), 1.74–1.50(m, 3H), 1.34–1.20(m, 2H),1.25(t, J=7.2 Hz, 3H), 0.96(d, J=6.6 Hz, 3H).

EXAMPLE 1(24)3-(5-(2-(2-(5-methylpyrazin-2-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.28 (hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 9.16(m, 1H),8.51(m, 1H), 7.13(dd, J=7.8, 7.8 Hz, 1H), 6.90(d, J=7.8 Hz, 1H), 6.79(d,J=7.8 Hz, 1H), 5.87(dd, J=4.5, 4.5 Hz, 1H), 4.28(t, J=6.3 Hz, 2H),4.13(q, J=7.2 Hz, 2H), 3.03(t, J=6.3 Hz, 2H), 2.80–2.60(m, 7H),2.53–2.46(m, 2H), 2.44(s, 3H), 2.22–2.13(m, 2H), 1.24(t, J=7.2 Hz, 3H).

EXAMPLE 1(25)3-(5-(2-(2-(1,2,3,6-tetrahydropyridin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ethyl ester

TLC: Rf 0.63 (hexane:ethyl acetate=1:1).

EXAMPLE 1(26)2-(5-(2-(2-phenyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)aceticacid ethyl ester

TLC: Rf 0.42 (hexane:ethyl acetate=3:1); NMR(CDCl₃): δ 8.01–7.94(m, 2H),7.48–7.37(m, 3H), 7.11(t, J=8.0 Hz, 1H), 6.82(d, J=8.0 Hz, 1H), 6.80(d,J=8.0 Hz, 1H), 5.98(t, J=4.6 Hz, 1H), 4.25(t, J=6.6 Hz, 2H), 4.12(q,J=7.2 Hz, 2H), 3.42–3.39(m, 2H), 2.99(t, J=7.2 Hz, 2H), 2.76(t, J=8.2Hz, 2H), 2.37(s, 3H), 2.33–2.19(m, 2H), 1.21(t, J=7.2 Hz, 3H).

EXAMPLE 1(27)2-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)aceticacid ethyl ester

TLC: Rf 0.57 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.86(d, J=8.1 Hz,2H), 7.23(d, J=8.1 Hz, 2H), 7.10(dd, J=7.8, 7.8 Hz, 1H), 6.81(m, 2H),5.97(t, J=4.5 Hz, 1H), 4.24(t, J=6.6 Hz, 2H), 4.13(q, J=7.2 Hz, 2H),3.46(s, 2H), 2.98(t, J=6.6 Hz, 2H), 2.76(t, J=8.4 Hz, 2H), 2.38(s, 3H),2.35(s, 3H), 2.27(m, 2H), 1.21(t, J=7.2 Hz, 3H).

EXAMPLE 1(28)2-(5-(2-(2-isopropyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)aceticacid ethyl ester

TLC: Rf 0.45 (hexane:ethyl acetate=2:1); NMR (CDCl₃): δ 7.10(dd, J=7.8,7.8 Hz, 1H), 6.86–6.74(m, 2H), 5.98(dd, J=4.5, 4.5 Hz, 1H), 4.15(q,J=6.9 Hz, 2H), 4.15(t, J=8.4 Hz, 2H), 3.40(d, J=1.2 Hz, 2H), 2.99(sept.,J=6.9 Hz, 1H), 2.88(t, J=6.6 Hz, 2H), 2.74(t, J=6.9 Hz, 2H),2.32–2.20(m, 2H), 2.24(s, 3H), 1.31(d, J=6.9 Hz, 6H), 1.22(t, J=6.9 Hz,3H).

EXAMPLE 1(29)2-(5-(2-(2-(4-cyclohexylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)aceticacid ethyl ester

TLC: Rf 0.63 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.94–7.84(m, 2H),7.32–7.22(m, 2H), 7.10(dd, J=8.1, 8.1 Hz, 1H), 6.86–6.76(m, 2H), 5.98(t,J=4.5 Hz, 1H), 4.24(t, J=6.6 Hz, 2H), 4.12(q, J=7.2 Hz, 2H), 3.40(d,J=1.2 Hz, 2H), 2.98(t, J=6.6 Hz, 2H), 2.76(t, J=8.1 Hz, 2H), 2.53(m,1H), 2.35(s, 3H), 2.32–2.20(m, 2H), 1.96–1.70(m, 5H), 1.54–1.26(m, 5H),1.21(t, J=7.2 Hz, 3H).

EXAMPLE 1(30)2-(5-(2-(2-(4-methylpiperazin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)aceticacid ethyl ester

TLC: Rf 0.21 (methanol:ethyl acetate=1:10); NMR(CDCl₃): δ 7.10(dd,J=8.1, 8.1 Hz, 1H), 6.81(d, J=8.1 Hz, 1H), 6.79(d, J=8.1 Hz, 1H),5.98(brt, 1H), 4.20(t, J=6.9 Hz, 2H), 4.13(q, J=6.9 Hz, 2H),3.44–3.36(m, 6H), 2.96(t, J=6.9 Hz, 2H), 2.76(dd, J=8.4, 8.4 Hz, 2H),2.50(m, 4H), 2.33(s, 3H), 2.26(s, 3H), 2.31–2.21(m, 2H), 1.22(t, J=6.9Hz, 3H).

EXAMPLE 1(31)2-(5-(2-(2-(piperidin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)aceticacid ethyl ester

TLC: Rf 0.58 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.10(dd, J=7.8,7.8 Hz, 1H), 6.85–6.76(m, 2H), 5.98(dd, J=4.8, 4.8 Hz, 1H), 4.20(t,J=6.6 Hz, 2H), 4.13(q, J=7.2 Hz, 2H), 3.40(m, 2H), 3.36(m, 4H), 2.95(t,J=6.6 Hz, 2H), 2.76(dd, J=8.4, 8.4 Hz, 2H), 2.33–2.20(m, 2H), 2.24(s,3H), 1.70–1.54(m, 6H), 1.20(t, J=7.2 Hz, 3H).

EXAMPLE 1(32)5-(5-(2-(2-phenyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)pentanoicacid methyl ester

TLC: Rf 0.52 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 8.02–7.94(m, 2H),7.48–7.37(m, 3H), 7.12(t, J=8.0 Hz, 1H), 6.87(d, J=8.0 Hz, 1H), 6.79(d,J=8.0 Hz, 1H), 5.84(t, J=4.4 Hz, 1H), 4.25(t, J=6.6 Hz, 2H), 3.65(s,3H), 2.99(t, J=6.6 Hz, 2H), 2.71(t, J=7.8 Hz, 2H), 2.43(t, J=7.6 Hz,2H), 2.38(s, 3H), 2.32(t, J=7.8 Hz, 2H), 2.25–2.11(m, 2H), 1.86–1.44(m,4H).

EXAMPLE 1(33)5-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)pentanoicacid methyl ester

TLC: Rf 0.41 (hexane:ethyl acetate=3:1); NMR(CDCl₃): δ 7.85(d, J=8 Hz,2H), 7.25(d, J=8 Hz, 2H), 7.10(m, 1H), 6.90–6.65(m, 2H), 5.85(t, J=7 Hz,1H), 4.25(t, J=7 Hz, 2H), 3.65(s, 3H), 3.00(t, J=7 Hz, 2H), 2.70(t, J=8Hz, 2H), 2.50–2.10(m, 12H), 1.80–1.50(m, 4H).

EXAMPLE 1(34)5-(5-(2-(2-(1,3-dioxaindan-5-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)pentanoicacid methyl ester

TLC: Rf 0.31 (hexane:ethyl acetate=3:1); NMR(CDCl₃): δ 7.55(dd, J=8, 1Hz, 1H), 7.45(d, J=1Hz, 1H), 7.10(dd, J=7.5, 7.5 Hz, 1H), 6.90–6.85(m,3H), 6.00(s, 2H), 5.85(t, J=7 Hz, 1H), 4.20(t, J=6.5 Hz, 2H), 3.65(s,3H), 3.00(t, J=6.5 Hz, 2H), 2.70,(t, J=8 Hz, 2H), 2.50–2.10(m, 9H),1.80–1.50(m, 4H).

EXAMPLE 1(35)5-(5-(2-(2-(4-dimethylaminophenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)pentanoicacid methyl ester

TLC: Rf 0.33 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.80(d, J=8 Hz,2H), 7.10(m, 1H), 6.90–6.70(m, 4H), 5.85(m, 1H), 4.20(t, J=6.5 Hz, 2H),3.65(s, 3H), 3.00(s, 6H), 2.95(m, 2H), 2.70(m, 2H), 2.50–2.10(m, 6H),1.80–1.50(m, 4H).

EXAMPLE 1(36)2,2-dimethyl-3-(5-(2-(2-phenyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.62 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 8.02–7.94(m, 2H),7.48–7.34(m, 3H), 7.08(t, J=8.1 Hz, ₁H), 6.90(d, J=8.1 Hz, 1H), 6.77(d,J=8.1 Hz, 1H), 5.83(t, J=4.8 Hz, 1H), 4.24(t, J=6.6 Hz, 2H), 3.46(s,3H), 2.99(t, J=6.6 Hz, 2H), 2.71(s, 2H), 2.68(t, J=5.1 Hz, 2H), 2.37(s,3H), 2.19–2.09(m, 2H), 1.13(s, 6H).

EXAMPLE 1(37)2,2-dimethyl-3-(5-(2-(2-(6-dimethylaminopyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.38 (hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 8.73(d, J=2.4 Hz,1H), 7.99(dd, J=9.0, 2.4 Hz, 1H), 7.08(dd, J=8.1, 8.1 Hz, 1H), 6.90(d,J=8.1 Hz, 1H), 6.77(d, J=8.1 Hz, 1H), 6.52(d, J=9.0 Hz, 1H), 5.83(t,J=4.5 Hz, 1H), 4.23(t, J=6.6 Hz, 2H), 3.46(s, 3H), 3.14(s, 6H), 2.96(t,J=6.6 Hz, 2H), 2.71(s, 2H), 2.68(t, J=8.1 Hz, 2H), 2.34(s, 3H),2.17–2.10(m, 2H), 1.13(s, 6H).

EXAMPLE 1(38)2,2-dimethyl-3-(5-(2-(2-isopropyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.63 (hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 7.08(dd, J=8.4,7.8 Hz, 1H), 6.89(d, J=7.8 Hz, 1H), 6.74(d, J=8.4 Hz, 1H), 5.83(m, 1H),4.16(t, J=6.6 Hz, 2H), 3.46(s, 3H), 2.99(quint., J=7.2 Hz, 1H), 2.89(t,J=6.6 Hz, 2H), 2.71(s, 2H), 2.66(t, J=8.1 Hz, 2H), 2.24(s, 3H),2.80–2.40(m, 2H), 1.31(d, J=7.2 Hz, 6H), 1.14(s, 6H).

EXAMPLE 1(39)2,2-dimethyl-3-(5-(2-(2-(6-(pyridin-1-yl)pyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.38 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 8.73(dd, J=2.4,0.6 Hz, 1H), 7.98(dd, J=9.0, 2.4 Hz, 1H), 7.08(dd, J=7.8, 7.8 Hz, 1H),6.90(d, J=7.8 Hz, 1H), 6.77(d, J=7.8 Hz, 1H), 6.65(dd, J=9.0, 0.6 Hz,1H), 5.83(t, J=4.5 Hz, 1H), 4.22(t, J=6.6 Hz, 2H), 3.68–3.54(m, 4H),3.46(s, 3H), 2.96(t, J=6.6 Hz, 2H), 2.71(s, 2H), 2.74–2.62(m, 2H),2.34(s, 3H), 2.20–2.06(m, 2H), 1.78–1.54(m, 6H), 1.13(s, 6H).

EXAMPLE 1(40)2,2-dimethyl-3-(5-(2-(2-(6-(morpholin-4-yl)pyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.65 (chloroform:methanol=8:1); NMR(CDCl₃): δ 8.76(dd, J=2.4,0.9 Hz, 1H), 8.04(dd, J=9.0, 2.4 Hz, 1H), 7.08(dd, J=7.8, 7.8 Hz, 1H),6.90(d, J=7.8 Hz, 1H), 6.77(d, J=7.8 Hz, 1H), 6.65(dd, J=9.0, 0.9 Hz,1H), 5.83(t, J=4.5 Hz, 1H), 4.23(t, J=6.6 Hz, 2H), 3.86–3.78(m, 4H),3.64–3.54(m, 4H), 3.46(s, 3H), 2.97(t, J=6.6 Hz, 2H), 2.76–2.62(m, 4H),2.35(s, 3H), 2.13(m, 2H), 1.78–1.54(m, 2H), 1.14(s, 6H).

EXAMPLE 1(41)2,2-dimethyl-3-(5-(2-(2-(6-methylpyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.53 (hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 9.08(d, J=1.8 Hz,1H), 8.12(dd, J=8.1, 1.8 Hz, 1H), 7.22(d, J=8.1 Hz, 1H), 7.08(dd, J=8.1,8.1 Hz, 1H), 6.90(d, J=8.1 Hz, 1H), 6.77(d, J=8.1 Hz, 1H), 5.83(t, J=4.5Hz, 1H), 4.24(t, J=6.6 Hz, 2H), 2.99(t, J=6.6 Hz, 2H), 2.71(s, 2H),2.67(t, J=8.1 Hz, 2H), 2.61(s, 3H), 2.38(s, 3H), 2.14(m, 2H), 1.13(s,6H).

EXAMPLE 1(42)2,2-dimethyl-3-(5-(2-(2-(morpholin-4-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.40 (hexane:ethyl acetate=5:1); NMR(CDCl₃): δ 7.08(dd, J=8.1,7.8 Hz, 1H), 6.89(d, J=7.8 Hz, 1H), 6.76(d, J=8.1 Hz, 1H), 5.83(t, J=4.8Hz, 1H), 4.20(t, J=6.9 Hz, 2H), 3.79(t, J=4.8 Hz, 4H), 3.37(t, J=4.8 Hz,4H), 2.96(t, J=6.9 Hz, 2H), 2.71(s, 2H), 2.67(t, J=7.2 Hz, 2H), 2.27(s,3H), 2.17–2.10(m, 2H), 1.14(s, 6H).

EXAMPLE 1(43)2,2-dimethyl-3-(5-(2-(2-(piperidin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.90 (hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 7.07(dd, J=7.8,7.8 Hz, 1H), 6.89(d, J=7.8 Hz, 1H), 6.76(d, J=8.1 Hz, 1H), 5.83(t, J=4.8Hz, 1H), 4.20(t, J=6.6 Hz, 2H), 3.46(s, 3H), 3.36(m, 4H), 2.95(t, J=6.6Hz, 2H), 2.71(s, 2H), 2.68(t, J=8.4 Hz, 2H), 2.25(s, 3H), 2.17–2.10(m,2H), 1.61(m, 6H), 1.14(s, 6H).

EXAMPLE 1(44)2,2-dimethyl-3-(5-(2-(2-(thiomorpholin-4-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.76 (hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 7.08(dd, J=8.1,7.8 Hz, 1H), 6.89(d, J=7.8 Hz, 1H), 6.75(d, J=8.1 Hz, 1H), 5.83(t, J=4.8Hz, 1H), 4.19(t, J=6.6 Hz, 2H), 3.76–3.73(m, 4H), 3.47(s, 3H), 2.94(t,J=6.6 Hz, 2H), 2.71–2.67(m, 8H), 2.25(s, 3H), 2.17–2.10(m, 2H), 1.14(s,6H).

EXAMPLE 1(45)2,2-dimethyl-5-(5-(2-(2-phenyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)pentanoicacid methyl ester

TLC: Rf 0.68 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 8.02–7.94(m, 2H),7.48–7.37(m, 3H), 7.11(t, J=7.8 Hz, 1H), 6.85(d, J=7.8 Hz, 1H), 6.78(d,J=7.8 Hz, 1H), 5.82(t, J=4.4 Hz, 1H), 4.25(t, J=6.6 Hz, 2H), 3.59(s,3H), 2.99(t, J=6.6 Hz, 2H), 2.71(t, J=7.6 Hz, 2H), 2.44–2.32(m, 2H),2.24–2.11(m, 2H), 1.65–1.33(m, 4H), 1.14(s, 6H).

EXAMPLE 1(46)2-benzyloxy-3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid methyl ester

TLC: Rf 0.27 (hexane:ethyl acetate=4:1); NMR(CDCl₃): δ 7.87(m, 2H),7.26–7.18(m, 7H), 7.08(dd, J=8.1, 8.1 Hz, 1H), 6.84(d, J=8.1 Hz, 1H),6.79(d, J=8.1 Hz, 1H), 5.95(dd, J=4.5, 4.5 Hz, 1H), 4.63(d, J=11.7 Hz,1H), 4.34(d, J=11.7 Hz, 1H), 4.26(t, J=6.6 Hz, 2H), 4.16(dd, J=9.0, 3.6Hz, 1H), 3.70(s, 3H), 3.04–2.58(m, 6H), 2.38(s, 3H), 2.37(s, 3H),2.24–2.14(m, 2H).

EXAMPLE 23-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

The compound (950 mg) prepared in Example 1 was dissolved in methanol(8.0 ml) and tetrahydrofuran (8.0 ml), and 2N aqueous sodium hydroxidesolution (3.3 ml) was added thereto, followed by stirring at roomtemperature overnight. The reaction mixture was acidified with 1Nhydrochloric acid, and extracted with a mixed solvent of ethyl acetateand tetrahydrofuran. The extract was washed with saturated saline, driedwith anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was recrystallized with a mixed solvent of ethylacetate and tetrahydrofuran to thereby obtain the compound of thepresent invention (745 mg) having the following physical data.

TLC: Rf 0.63 (chloroform:methanol=8:1); NMR(DMSO-d₆): δ 7.79(d, J=8.2Hz, 2H), 7.29(d, J=8.2 Hz, 2H), 7.14(dd, J=8.0, 8.0 Hz, 1H),6.97–6.78(m, 2H), 5.84(brt, 1H), 4.19(t, J=5.8 Hz, 2H), 2.91(t, J=5.8Hz, 2H), 2.75–2.20(m, 6H), 2.33(s, 3H), 2.36(s, 3H), 2.20–1.94(m, 2H).

EXAMPLE 2(1) TO EXAMPLE 2(41)

The following compounds of the present invention were obtained in thesame manner as in Example 2 using the compound prepared in Example 1 (1)to Example 1(9), Example 1 (11) to Example 1(27) and Example 1(32) toExample 1(46) instead of the compound prepared in Example 1, ifnecessary followed by converting to a corresponding salt by a knownmethod.

EXAMPLE 2(1)3-(5-(2-(2-phenyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR(CDCl₃): δ 8.02–7.94(m, 2H),7.46–7.37(m, 3H), 7.13(t, J=8.0 Hz, 1H), 6.88(d, J=8.0 Hz, 1H), 6.81(d,J=8.0 Hz, 1H), 5.89(brt, J=4.6 Hz, 1H), 4.25(t, J=6.6 Hz, 2H), 3.00(t,J=6.6 Hz, 2H), 2.83–2.52(m, 6H), 2.37(s, 3H), 2.27–2.12(m, 2H).

EXAMPLE 2(2)3-(5-(2-(2-(6-dimethylaminopyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR(CDCl₃): δ 8.73(dd, J=2.4,0.4 Hz, 1H), 8.00(dd, J=9.0, 2.4 Hz, 1H), 7.12(t, J=8.0 Hz, 1H), 6.89(d,J=8.0 Hz, 1H), 6.80(d, J=8.0 Hz, 1H), 6.53(dd, J=9.0, 0.4 Hz, 1H),5.89(brt, J=4.4 Hz, 1H), 4.23(t, J=6.6 Hz, 2H), 3.14(s, 6H), 2.97(t,J=6.6 Hz, 2H), 2.83–2.52(m, 6H), 2.34(s, 3H), 2.26–2.12(m, 2H).

EXAMPLE 2(3)3-(5-(2-(2-(1,3-dioxaindan-5-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.61 (chloroform:methanol=8:1); NMR(DMSO-d₆): δ 7.43(d, J=8.3Hz, 1H), 7.35(s, 1H), 7.14(dd, J=8.0, 8.0 Hz, 1H), 7.01(d, J=8.3 Hz,1H), 6.96–6.75(m, 2H), 6.09(s, 2H), 5.84(brt, 1H), 4.18(t, J=6.0 Hz,2H), 2.90(t, J=6.0 Hz, 2 H ), 2.75–2.20(m, 6H), 2.31(s, 3H),2.20–1.94(m, 2H).

EXAMPLE 2(4)3-(5-(2-(2-(4-t-butylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.47 (chloroform:methanol=10:1); NMR(CDCl₃): δ 7.90(d, J=8.6 Hz,2H), 7.44(d, J=8.6 Hz, 2H), 7.12(dd, J=7.8, 7.6 Hz, 1H), 6.88(d, J=7.6Hz, 1H), 6.80(d, J=7.8 Hz, 1H), 5.88(t, J=6.6 Hz, 1H), 4.24(t, J=6.4 Hz,2H), 2.99(t, J=6.4 Hz, 2H), 2.84–2.50(m, 6H), 2.35(s, 3H), 2.19(m, 2H),1.33(s, 9H).

EXAMPLE 2(5)3-(5-(2-(2-(6-(morpholin-4-yl)pyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.32 (chloroform:methanol=10:1); NMR(DMSO-d₆): δ 8.61(d, J=2.4Hz, 1H), 7.97(dd, J=8.8, 2.4 Hz, 1H), 7.13(dd, J=8.4, 7.4 Hz, 1H),6.96–6.82(m, 3H), 5.84(t, J=4.4 Hz, 1H), 4.17(t, J=6.4 Hz, 2H), 3.68(m,4H), 3.53(m, 4H), 2.89(t, J=6.4 Hz, 2H), 2.69–2.45(m, 4H), 2.43–2.28(m,2H), 2.31(s, 3H), 2.10(m, 2H).

EXAMPLE 2(6)3-(5-(2-(2-(4-dimethylaminophenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.50 (chloroform:methanol=9:1); NMR(CDCl₃): δ 7.80(d, J=9 Hz,2H), 7.15(m, 1H), 6.90–6.70(m, 4H), 5.90(t, J=4 Hz, 1H), 4.25(t, J=7 Hz,2H), 3.00(s, 6H), 2.95(t, J=7 Hz, 2H), 2.80–2.50(m, 6H), 2.35(s, 3H),2.20(m, 2H).

EXAMPLE 2(7)3-(5-(2-(2-isopropyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.43 (chloroform:methanol=9:1); NMR(CDCl₃): δ 7.15(dd, J=7.5,7.5 Hz, 1H), 6.85(d, J=7.5 Hz, 1H), 6.80(d, J=7.5 Hz, 1H), 5.90(t, J=4Hz, 1H), 4.20(t, J=6 Hz, 2H), 3.00(m, 1H), 2.90(t, J=6 Hz, 2H), 2.75(m,2H), 2.65(t, J=8.5 Hz, 2H), 2.55(t, J=8.5 Hz, 2H), 2.20(s, 3H), 2.20(m,2H), 1.30(d, J=6 Hz, 6H).

EXAMPLE 2(8)3-(5-(2-(2-(4-trifluoromethylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.60 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 8.10(d, J=8 Hz,2H), 7.85(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.95–6.85(m, 2H),5.85(m, 1H), 4.20(t, J=6 Hz, 2H), 2.95(t, J=6 Hz, 2H), 2.70–2.50(m, 4H),2.40(s, 3H), 2.40(m, 2H), 2.10(m, 2H).

EXAMPLE 2(9)3-(5-(2-(2-(4-trifluoromethyloxyphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.51 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 8.00(d, J=9 Hz,2H), 7.50(d, J=9 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.95–6.85(m, 2H),5.85(m, 1H), 4.20(t, J=6 Hz, 2H), 2.95(t, J=6 Hz, 2H), 2.70–2.50(m, 4H),2.40(m, 2H), 2.40(s, 3H), 2.10(m, 2H).

EXAMPLE 2(10)3-(5-(2-(2-(4-chlorophenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.60 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 7.95(d, J=8 Hz,2H), 7.60(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.95(d, J=8 Hz, 1H),6.90(d, J=8 Hz, 1H), 5.85(t, J=4 Hz, 1H), 4.20(t, J=6 Hz, 2H), 2.95(t,J=6 Hz, 2H), 2.65–2.50(m, 6H), 2.40(s, 3H), 2.10(m, 2H).

EXAMPLE 2(11)3-(5-(2-(2-(4-methylthiophenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.49 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 7.80(d, J=8 Hz,2H), 7.35(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.95(d, J=8 Hz, 1H),6.90(d, J=8 Hz, 1H), 5.85(t, J=4 Hz, 1H), 4.20(t, J=7 Hz, 2H), 2.95(t,J=7 Hz, 2H), 2.65–2.55(m, 4H), 2.50(s, 3H), 2.40(m, 2H), 2.35(s, 3H),2.10(m, 2H).

EXAMPLE 2(12)3-(5-(2-(2-(4-isopropylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.58 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 7.80(d, J=8 Hz,2H), 7.35(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.90(d, J=8 Hz, 1H),6.85(d, J=8 Hz, 1H), 5.85(t, J=4 Hz, 1H), 4.20(t, J=6 Hz, 2H),3.00–2.90(m, 3H), 2.65–2.50(m, 4H), 2.40–2.35(m, 2H), 2.35(s, 3H),2.10(m, 2H), 1.20(d, J=8 Hz, 6H).

EXAMPLE 2(13)3-(5-(2-(2-(4-propylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.53 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 7.80(d, J=8 Hz,2H), 7.30(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.90(d, J=8 Hz, 1H),6.85(d, J=8 Hz, 1H), 5.85(t, J=4 Hz, 1H), 4.20(t, J=6 Hz, 2H), 2.95(t,J=6 Hz, 2H), 2.65–2.50(m, 8H), 2.40–2.35(m, 2H), 2.35(s, 3H), 2.10(m,2H), 0.90(t, J=8 Hz, 3H).

EXAMPLE 2(14)3-(5-(2-(2-(2,2-difluoro-1,3-dioxaindan-5-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.51 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 7.85(m, 1H),7.80(m, 1H), 7.55(d, J=8 Hz, 1H), 7.15(dd, J=8, 8 Hz, 1H), 6.90(d, J=8Hz, 1H), 6.85(d, J=8 Hz, 1H), 5.85(t, J=4 Hz, 1H), 4.20(t, J=7 Hz, 2H),2.95(t, J=7 Hz, 2H), 2.65–2.50(m, 4H), 2.40–2.35(m, 2H), 2.35(s, 3H),2.10(m, 2H).

EXAMPLE 2(15)3-(5-(2-(2-(6-diethylaminopyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.54 (chloroform:methanol=8:1); NMR(DMSO-d₆): δ 8.56(d, J=2.4Hz, 1H), 7.88(dd, J=9.0, 2.4 Hz, 1H), 7.13(dd, J=7.8, 7.8 Hz, 1H),6.89(d, J=7.8 Hz, 1H), 6.86(d, J=7.8 Hz, 1H), 6.65(d, J=9.0 Hz, 1H),5.84(dd, J=4.2, 4.2 Hz, 1H), 4.17(t, J=6.3 Hz, 2H), 3.51(q, J=6.9 Hz,4H), 3.32(brs, 1H), 2.88(t, J=6.9 Hz, 2H), 2.70–2.46(m, 4H), 2.36(t,J=7.2 Hz, 2H), 2.30(s, 3H), 2.18–2.00(m, 2H), 1.10(t, J=6.9 Hz, 6H).

EXAMPLE 2(16)3-(5-(2-(2-(piperidin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid hydrochloride

TLC: Rf 0.55 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 12.10(br, 1H),7.13(t, J=8.1 Hz, 1H), 6.87(d, J=8.1 Hz, 1H), 6.85(d, J=8.1 Hz, 1H),5.85(t, J=4.5 Hz, 1H), 4.13(t, J=6.6 Hz, 2H), 3.39–3.22(m, 4H), 2.83(t,J=6.6 Hz, 2H), 2.61(t, J=7.2 Hz, 2H), 2.55(t, J=7.8 Hz, 2H), 2.36(t,J=7.8 Hz, 2H), 2.18(s, 3H), 2.14–2.04(m, 2H), 1.58–1.48(m, 6H).

EXAMPLE 2(17)3-(5-(2-(2-(4-methylpiperazin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid hydrochloride

TLC: Rf 0.30 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 12.05(br, 1H),7.13(t, J=8.1 Hz, 1H), 6.86(d, J=8.1 Hz, 1H), 6.85(d, J=8.1 Hz, 1H),5.85(t, J=4.2 Hz, 1H), 4.13(t, J=6.6 Hz, 2H), 3.27(t, J=4.8 Hz, 4H),2.84(t, J=6.6 Hz, 2H), 2.61(t, J=7.5 Hz, 2H), 2.55(t, J=8.1 Hz, 2H),2.41–2.32(m, 6H), 2.19(s, 6H), 2.14–2.04(m, 2H).

EXAMPLE 2(18)3-(5-(2-(2-(morpholin-4-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid hydrochloride

TLC: Rf 0.45 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 12.02(br, 1H),7.13(t, J=7.8 Hz, 1H), 6.86(d, J=7.8 Hz, 1H), 6.85(d, J=7.8 Hz, 1H),5.85(t, J=4.2 Hz, 1H), 4.14(t, J=6.3 Hz, 2H), 3.66(t, J=4.8 Hz, 4H),3.25(t, J=4.8 Hz, 4H), 2.85(t, J=6.3 Hz, 2H), 2.61(t, J=7.5 Hz, 2H),2.55(t, J=8.1 Hz, 2H), 2.36(t, J=8.1 Hz, 2H), 2.20(s, 3H), 2.14–2.04(m,2H).

EXAMPLE 2(19)3-(5-(2-(2-(thiomorpholin-4-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid hydrochloride

TLC: Rf 0.45 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 12.09(br, 1H),7.13(t, J=7.8 Hz, 1H), 6.86(d, J=7.8 Hz, 1H), 6.85(d, J=7.8 Hz, 1H),5.85(t, J=4.2 Hz, 1H), 4.14(t, J=6.6 Hz, 2H), 3.67 –3.58(m, 4H), 2.84(t,J=6.6 Hz, 2H), 2.66–2.49(m, 8H), 2.36(t, J=8.1 Hz, 2H), 2.19(s, 3H),2.15–2.05(m, 2H).

EXAMPLE 2(20)3-(5-(2-(2-(6-methylpyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid hydrochloride

TLC: Rf 0.48 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 12.09(br, 1H),8.94(d, J=2.1 Hz, 1H), 8.11(dd, J=8.1, 2.1 Hz, 1H), 7.37(d, J=8.1 Hz,1H), 7.14(t, J=8.1 Hz, 1H), 6.90(d, J=8.1 Hz, 1H), 6.85(d, J=8.1 Hz,1H), 5.84(t, J=4.2 Hz, 1H), 4.20(t, J=6.0 Hz, 2H), 2.93(t, J=6.0 Hz,2H), 2.61(t, J=7.5 Hz, 2H), 2.56(t, J=8.4 Hz, 2H), 2.51(s, 3H), 2.40(t,J=7.5 Hz, 2H), 2.35(s, 3H), 2.14–2.04(m, 2H).

EXAMPLE 2(21)3-(5-(2-(2-(1,5-dimethylpyrazol-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid hydrochloride

TLC: Rf 0.39 (chloroform:methanol=9:1); NMR(DMSO-d₆): δ 12.09(br, 1H),7.14(t, J=8.1 Hz, 1H), 6.89(d, J=8.1 Hz, 1H), 6.86(d, J=8.1 Hz, 1H),6.45(s, 1H), 5.84(t, J=4.2 Hz, 1H), 4.17(t, J=6.3 Hz, 2H), 3.76(s, 3H),2.88(t, J=6.3 Hz, 2H), 2.61(t, J=7.5 Hz, 2H), 2.54(t, J=7.8 Hz, 2H),2.36(t, J=7.5 Hz, 2H), 2.28(s, 3H), 2.27(s, 3H), 2.14–2.04(m, 2H).

EXAMPLE 2(22)3-(5-(2-(2-(4-methylpiperidin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.55 (ethyl acetate); NMR(DMSO-d₆): δ 7.04(t, J=7.8 Hz, 1H),6.77(d, J=7.8 Hz, 1H), 6.76(d, J=7.8 Hz, 1H), 5.78–5.72(m, 1H), 4.04(t,J=6.6 Hz, 2H), 3.70–3.58(m, 2H), 2.84–2.74(m, 2H), 2.80(bs, 1H), 2.74(t,J=6.6 Hz, 2H), 2.55–2.40(m, 4H), 2.30–2.23(m, 2H), 2.08(s, 3H),2.05–1.95(m, 2H), 1.60–1.35(m, 3H), 1.14–0.94(m, 2H), 0.80(d. J=6.6 Hz,3H).

EXAMPLE 2(23)3-(5-(2-(2-(5-methylpyrazin-2-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.51 (chloroform:methanol=10:1); NMR(DMSO-d₆): δ 12.08(br, 1H),9.06(m, 1H), 8.60(m, 1H), 7.14(dd, J=8.1, 8.1 Hz, 1H), 6.90(d, J=8.1 Hz,1H), 6.86(d, J=8.1 Hz, 1H), 5.84(dd, J=4.5, 4.5 Hz, 1H), 4.22(t, J=6.3Hz, 2H), 2.97(t, J=6.3 Hz, 2H), 2.65–2.52(m, 7H), 2.38(s, 3H),2.40–2.32(m, 2H), 2.13–2.04(m, 2H).

EXAMPLE 2(24)3-(5-(2-(2-(1,2,3,6-tetrahydropyridin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.40 (chloroform:methanol=9:1); NMR(CDCl₃): δ 7.12(t, J=7.8 Hz,1H), 6.87(d, J=7.8 Hz, 1H), 6.80(d, J=7.8 Hz, 1H), 5.92–5.84(m, 2H),5.78–5.70(m, 1H), 4.21(t, J=6.9 Hz, 2H), 3.86(dt, J=5.4, 2.7 Hz, 2H),3.54(t, J=5.7 Hz, 2H), 2.97(t, J=6.9 Hz, 2H), 2.80–1.60(br, 1H),2.80–2.72(m, 2H), 2.70(t, J=8.1 Hz, 2H), 2.60–2.54(m, 2H), 2.30–2.18(m,4H), 2.26(s, 3H).

EXAMPLE 2(25)2-(5-(2-(2-phenyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)aceticacid

TLC: Rf 0.54 (chloroform:methanol=10:1); NMR(CDCl₃): δ 8.01–7.92(m, 2H),7.48–7.36(m, 3H), 7.09(t, J=8.0 Hz, 1H), 6.83(d, J=8.0 Hz, 1H), 6.76(d,J=8.0 Hz, 1H), 6.00(t, J=4.8 Hz, 1H), 4.20(t, J=6.4 Hz, 2H), 3.43(brs,2H), 2.98(t, J=6.4 Hz, 2H), 2.75(t, J=8.0 Hz, 2H), 2.35(s, 3H),2.32–2.18(m, 2H).

EXAMPLE 2(26)2-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)aceticacid

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR(CDCl₃): δ 7.86(d, J=8.1 Hz,2H), 7.22(d, J=8.1 Hz, 2H), 7.09(dd, J=7.8, 7.8 Hz, 1H), 6.83(d, J=7.8Hz, 1H), 6.78(d, J=7.8 Hz, 1H), 6.00(t, J=4.5 Hz, 1H), 4.02(t, J=6.6 Hz,2H), 3.44(s, 2H), 2.97(t, J=6.6 Hz, 2H), 2.75(t, J=6.6 Hz, 2H), 2.38(s,3H), 2.34(s, 3H), 2.26(m, 2H).

EXAMPLE 2(27)5-(5-(2-(2-phenyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)pentanoicacid

TLC: Rf 0.55 (chloroform:methanol=9:1); NMR(CDCl₃): δ 8.02–7.94(m, 2H),7.48–7.37(m, 3H), 7.12(t, J=8.0 Hz, 1H), 6.87(t, J=8.0 Hz, 1H), 6.79(d,J=8.0 Hz, 1H), 5.84(t, J=4.6 Hz, 1H), 4.25(t, J=6.4 Hz, 2H), 3.00(t,J=6.4 Hz, 2H), 2.71(t, J=7.4 Hz, 2H), 2.50–2.30(m, 7H), 2.25–2.10(m,2H), 1.78–1.45(m, 4H).

EXAMPLE 2(28)5-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)pentanoicacid

TLC: Rf 0.27 (chloroform:methanol=20:1); NMR(CDCl₃): δ 7.85(d, J=8 Hz,2H), 7.20(d, J=8 Hz, 2H), 7.15(dd, J=8, 8 Hz, 1H), 6.85(d, J=8 Hz, 1H),6.80(d, J=8 Hz, 1H), 5.85(t, J=7 Hz, 1H), 4.25(t, J=7 Hz, 2H), 3.00(t,J=7 Hz, 2H), 2.70(t, J=8 Hz, 2H), 2.50–2.30(m, 4H), 2.40(s, 3H), 2.30(s,3H), 2.20(m, 2H), 1.80–1.50(m, 4H).

EXAMPLE 2(29)5-(5-(2-(2-(1,3-dioxaindan-5-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)pentanoicacid

TLC: Rf 0.20 (chloroform:methanol=20:1); NMR(CDCl₃+CD₃OD): δ 7.55(dd,J=8 Hz, 1H), 7.45(d, J=l Hz, 1H), 7.15(dd, J=7.5, 7.5 Hz, 1H), 6.90(d,J=7.5 Hz, 1H), 6.85(d, J=8 Hz, 1H), 6.80(d, J=7.5 Hz, 1H), 6.00(s, 2H),5.85(t, J=4 Hz, 1H), 4.20(t, J=6.5 Hz, 2H), 2.95(t, J=6.5 Hz, 2H),2.70(t, J=8 Hz, 2H), 2.50–2.20(m, 4H), 2.30(s, 3H), 2.20(m, 2H),1.80–1.45(m, 4H).

EXAMPLE 2(30)5-(5-(2-(2-(4-dimethylaminophenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)pentanoicacid

TLC: Rf 0.55 (chloroform:methanol=9:1); NMR(CDCl₃): δ 7.80(d, J=8 Hz,2H), 7.10(m, 1H), 6.90–6.70(m, 4H), 5.85(m, 1H), 4.20(t, J=6.5 Hz, 2H),3.00(s, 6H), 2.95(m, 2H), 2.70(m, 2H), 2.50–2.10(m, 6H), 1.80–1.50(m,4H).

EXAMPLE 2(31)2,2-dimethyl-3-(5-(2-(2-phenyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.35 (hexane:ethyl acetate=2:1); NMR(DMSO-d₆): δ 12.07(br, 1H),7.93–7.86(m, 2H), 7.53–7.42(m, 3H), 7.09(t, J=8.1 Hz, 1H), 6.95(d, J=8.1Hz, 1H), 6.86(d, J=8.1 Hz, 1H), 5.84(t, J=4.2 Hz, 1H), 4.19(t, J=6.3 Hz,2H), 2.93(t, J=6.3 Hz, 2H), 2.65(s, 2H), 2.55(t, J=7.8 Hz, 2H), 2.34(s,3H), 2.08–1.98(m, 2H), 0.99(s, 6H).

EXAMPLE 2(32)2,2-dimethyl-3-(5-(2-(2-(6-dimethylaminopyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.62 (hexane:ethyl acetate=1:19); NMR(CDCl₃): δ 8.73(d, J=2.7Hz, 1H), 8.05(dd, J=8.7, 2.7 Hz, 1H), 7.08(dd, J=7.8, 7.8 Hz, 1H),6.96(d, J=7.8 Hz, 1H), 6.76(d, J=7.8 Hz, 1H), 6.58(d, J=8.7 Hz, 1H),5.91(t, J=4.5 Hz, 1H), 4. 23(t, J=6.3 Hz, 2H), 3.20(s, 6H), 2.96(t,J=6.3 Hz, 2H), 2.76(s, 2H), 2.68(t, J=7.5 Hz, 2H), 2.34(s, 3H),2.18–2.11(m, 2H), 1.15(s, 6H).

EXAMPLE 2(33)2,2-dimethyl-3-(5-(2-(2-isopropyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ½ calcium salt

TLC: Rf 0.86 (hexane:ethyl acetate=1:19); NMR(DMSO-d₆): δ 7.06(m, 1H),7.58(d, J=7.5 Hz, 1H), 6.80(d, J=8.1 Hz, 1H), 5.88(m, 1H), 4.10(t, J=6.9Hz, 2H), 2.94(quint, J=6.9 Hz, 1H), 2.79(t, J 6.6 Hz, 2H), 2.63(s, 2H),2.50(m, 2H), 2.19(s, 3H), 2.05(m, 2H), 1.20(d, J=6.9 Hz, 6H), 0.89(s,6H).

EXAMPLE 2(34)2,2-dimethyl-3-(5-(2-(2-(6-(pyridin-1-yl)pyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid sodium salt

TLC: Rf 0.59 (chloroform:methanol=8:1); NMR(DMSO-d₆): δ 8.57(d, J=2.1Hz, 1H), 7.90(dd, J=9.0, 2.1 Hz, 1H), 7.06(dd, J=8.1, 7.5 Hz, 1H),6.97(d, J=7.5 Hz, 1H), 6.87(d, J=9.0 Hz, 1H), 6.81(d, J=8.1 Hz, 1H),5.84(t, J=4.5 Hz, 1H), 4. 15(t, J=6.3 Hz, 2H), 3.68–3.50(m, 4H), 2.88(t,J=6.3 Hz, 2H), 2.66–2.48(m, 4H), 2.29(s, 3H), 2.14–1.92(m, 2H),1.70–1.38(m, 6H), 0.85(s, 6H).

EXAMPLE 2(35)2,2-dimethyl-3-(5-(2-(2-(6-(morpholin-4-yl)pyridin-3-y)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid sodium salt

TLC: Rf 0.56 (chloroform:methanol=8:1); NMR(DMSO-d₆): δ 8.61(d, J=2.1Hz, 1H), 7.97(dd, J=9.0, 2.1 Hz, 1H), 7.06(dd, J=8.1, 7.5 Hz, 1H),6.97(d, J=8.1 Hz, 1H), 6.91(d, J=9.0 Hz, 1H), 6.81(d, J=7.5 Hz, 1H),5.84(t, J=4.5 Hz, 1H), 4.16(t, J=6.0 Hz, 2H), 3.76–3.62(m, 4H),3.60–3.44(m, 4H), 2.89(t, J=6.0 Hz, 2H), 2.64–2.48(m, 4H), 2.31(s, 3H),2.14–1.92(m, 4H), 0.84(s, 6H).

EXAMPLE 2(36)2,2-dimethyl-3-(5-(2-(2-(6-methylpyridin-3-yl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.48 (hexane:ethyl acetate=1:19); NMR(CDCl₃): δ 9.05(d, J=1.8Hz, 1H), 8.13(dd, J=8.4, 1.8 Hz, 1H), 7.22(d, J=8.1 Hz, 1H), 7.07(dd,J=8.1, 8.1, Hz, 1H), 6.96(d, J=8.1 Hz, 1H), 6.75(d, J=8.4 Hz, 1H),5.91(m, 1H), 4.24(t, J=6 .6 Hz, 2H), 2.98(t, J=6.6 Hz, 2H), 2.76(s, 2H),2.68(t, J=7.8 Hz, 2H), 2.60(s, 3H), 2.38(s, 3H), 2.18–2.11(m, 2H),1.15(s, 6H).

EXAMPLE 2(37)2,2-dimethyl-3-(5-(2-(2-(morpholin-4-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.72 (hexane:ethyl acetate=1:19); NMR(CDCl₃): δ 7.08(dd, J=8.1,7.5 Hz, 1H), 6.95(d, J=7.5 Hz, 1H), 6.76(d, J=8.1 Hz, 1H), 5.90(t, J=4.8Hz, 1H), 4.21(t, J=6.6 Hz, 2H), 3.79(t, J=4.8 Hz, 4H), 3.39(m, 4H),2.98(t, J=6.6 Hz, 2H), 2.76(s, 2H), 2.67(t, J=7.8 Hz, 2H), 2.27(s, 3H),2.18–2.11(m, 2H), 1.14(s, 6H).

EXAMPLE 2(38)2,2-dimethyl-3-(5-(2-(2-(piperidin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.76 (chloroform:methanol=19:1); NMR(CDCl₃): δ 7.07(dd, J=7.8,7.8 Hz, 1H), 6.94(d, J=7.8 Hz, 1H), 6.76(d, J=7.8 Hz, 1H), 5.90(t, J=4.8Hz, 1H), 4.20(t, J=6.9 Hz, 2H), 3.36(m, 4H), 2.95(t, J=6.9 Hz, 2H),2.76(s, 2H), 6.69(t, J=8.4 Hz, 2H), 2.24(s, 3H), 2.18–2.11(m, 2H),1.62(m, 6H), 1.14(s, 6H).

EXAMPLE 2(39)2,2-dimethyl-3-(5-(2-(2-(thiomorpholin-4-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.73 (chloroform:methanol=19:1); NMR(CDCl₃): δ 7.08(dd, J=8.7,8.7 Hz, 1H), 6.95(d, J=8.7 Hz, 1H), 6.76(d, J=8.7 Hz, 1H), 5.91(m, 1H),4.20(t, J=6.6 Hz, 2H), 3.75(m, 4H), 2.94(t, J=6.6 Hz, 2H), 2.77(s, 2H),2.68(m, 6H), 2.25(s, 3H), 2.15(m, 2H), 1.15(s, 6H).

EXAMPLE 2(40)2,2-dimethyl-5-(5-(2-(2-phenyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)pentanoicacid

TLC: Rf 0.49 (chloroform:methanol=10:1); NMR(CDCl₃): δ 8.01–7.92(m, 2H),7.48–7.36(m, 3H), 7.10(t, J=8.0 Hz, 1H), 6.86(d, J=8.0 Hz, 1H), 6.77(d,J=8.0 Hz, 1H), 5.83(t, J=4.6 Hz, 1H), 4.24(t, J=6.6 Hz, 2H), 2.99(t,J=6.6 Hz, 2H), 2.7 0(t, J=7.8 Hz, 2H), 2.46–2.32(m, 2H), 2.36(s, 3H),2.24–2.11(m, 2H), 1.67–1.40(m, 4H),1.17(s, 6H).

EXAMPLE 2(41)2-benzyloxy-3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR(CDCl₃): δ 7.86(m, 2H),7.34–7.12(m, 7H), 7.08(dd, J=8.1, 8.1 Hz, 1H), 6.89(d, J=8.1 Hz, 1H),6.80(d, J=8.1 Hz, 1H), 5.99(dd, J=4.5, 4.5 Hz, 1H), 4.57(d, J=11.7 Hz,1H), 4.41(d, J=11.7 Hz , 1H), 4.29–4.20(m, 2H), 4.16(dd, J=9.0, 3.6 Hz,1H), 3.10(m, 1H), 3.00(t, J=6.6 Hz, 2H), 2.90–2.66(m, 2H), 2.60(m, 1H),2.38(s, 3H), 2.36(s, 3H), 2.25–2.12(m, 2H).

EXAMPLE 32-(5-(2-(2-(4-cyclohexylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)ethanol

To a tetrahydrofuran (7.0 ml) suspension of lithium aluminum hydride(147 mg), a tetrahydrofuran (12 ml) solution of the compound (1.93 g)prepared in Example 1(29) was added dropwise at 0° C., followed bystirring at room temperature for 1.5 hours. The reaction mixture wascooled to 0° C., and a saturated aqueous sodium sulfate solution wasadded thereto. The reaction mixture was dried with anhydrous magnesiumsulfate, and concentrated. The residue was recrystallized with a mixedsolvent of hexane and ethyl acetate to thereby obtain the compound ofthe present invention (1.26 g) having the following physical data.

TLC: Rf 0.50 (hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 7.92–7.84(m, 2H),7.30–7.22(m, 2H), 7.13(dd, J=8.1, 8.1 Hz, 1H), 7.89(d, J=8.1 Hz, 1H),6.81(d, J=8.1 Hz, 1H), 5.95(t, J=4.5 Hz, 1H), 4.25(t, J=6.6 Hz, 2H),3.82–3.68(m, 2H), 2.98(t, J=6.6 Hz, 2H), 2.78–2.66(m, 4H), 2.53(m, 1H),2.36(s, 3H), 2.30–2.16(m, 2H), 1.96–1.70(m, 5H), 1.54–1.14(m, 5H).

EXAMPLE 3(1) TO EXAMPLE 3(5)

The following compounds of the present invention were obtained in thesame manner as in Example 3 using the compound prepared in Example1(27), Example 1(28), Example 1(30), Example 1(31) and Example 2 insteadof the compound prepared in Example 1(29).

EXAMPLE 3(1)2-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)ethanol

TLC: Rf 0.27 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.86(d, J=8.4 Hz,2H), 7.23(d, J=8.4 Hz, 2H), 7.12(dd, J=8.1, 8.1 Hz, 1H), 6.89(d, J=8.1Hz, 1H), 6.81(d, J=8.1 Hz, 1H), 5.94(t, J=4.5 Hz, 1H), 4.25(t, J=6.6 Hz,2H), 3.76(m, 2H), 2.98(t, J=6.6 Hz, 2H), 2.78–2.67(m, 4H), 2.38(s, 3H),2.36(s, 3H), 2.22(m, 2H).

EXAMPLE 3(2)2-(5-(2-(2-isopropyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)ethanol

TLC: Rf 0.34 (hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 7.12(dd, J=7.8,7.8 Hz, 1H), 6.89(d, J=7.8 Hz, 1H), 6.79(dd, J=7.8, 0.9 Hz, 1H),5.95(dd, J=4.5, 4.5 Hz, 1H), 4.17(t, J=6.6 Hz, 2H), 3.82–3.70(m, 2H),2.99(sept., J=6.9 Hz, 1H), 2.89(t, J=6.6 Hz, 2H), 2.76–2.66(m, 4H),2.28–2.16(m, 2H), 2.25(s, 3H), 1.31(d, J=6.9 Hz, 6H).

EXAMPLE 3(3)2-(5-(2-(2-(4-methylpiperazin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)ethanol

TLC: Rf 0.26(methanol:ethyl acetate=1:5); NMR(CDCl₃): δ 7.12(dd, J=8.1,8.1 Hz, 1H), 6.88(d, J=8.1 Hz, 1H), 6.80(d, J=8.1 Hz, 1H), 5.95(brt,1H), 4.22(t, J=6.6 Hz, 2H), 3.76(t, J=6.6 Hz, 2H), 3.40(brt, 4H),2.96(t, J=6.6 Hz, 2H), 2.76–2.67(m, 4H), 2.50(brt, 4H), 2.33(s, 3H),2.26(s, 3H), 2.26–2.17(m, 2H).

EXAMPLE 3(4)2-(5-(2-(2-(piperidin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)ethanol

TLC: Rf 0.27 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.12(dd, J=7.8,7.8 Hz, 1H), 6.88(d, J=7.8 Hz, 1H), 6.81(d, J=7.8 Hz, 1H), 5.95(dd,J=4.5, 4.5 Hz, 1H), 4.21(t, J=6.9 Hz, 2H), 3.75(m, 2H), 3.36(m, 4H),2.96(t, J=6.9 Hz, 2H), 2.77–2.68(m, 4H), 2.25(s, 3H), 2.27–2.18(m, 2H),1.72–1.53(m, 6H).

EXAMPLE 3(5)3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanol

TLC: Rf 0.55 (ethyl acetate:hexane=2:1); NMR(CDCl₃): δ 7.86(d, J=8.1 Hz,2H), 7.23(d, J=8.1 Hz, 2H), 7.12(t, J=7.8 Hz, 1H), 6.91 (d, J=7.8 Hz,1H), 6.80(d, J=7.8 Hz, 1H), 5.90–5.84(m, 1H), 4.25(t, J=6.6 Hz, 2H),3.68(t, J=6.6 Hz, 2H), 2.99(t, J=6.6 Hz, 2H), 2.71(t, J=7.8 Hz, 2H),2.52(t, J=7.8 Hz, 2H), 2.39(s, 3H), 2.36(s, 3H), 2.24–2.14(m, 2H),1.78(quint, J=7.8 Hz, 2H), 1.58(s, 1H).

EXAMPLE 42-(5-(2-(2-(4-cyclohexylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)acetaldehyde

To a mixed solution of the compound (1.20 g) prepared in Example 3 inethyl acetate (12 ml) and dimethylsulfoxide (5.0 ml),diisopropylethylamine (2.7 ml) was added, and a dimethylsulfoxide (6.5ml) solution of sulfur trioxide-pyridine complex (1.25 g) was addeddropwise thereto at −10° C., followed by stirring at −10° C. for 2hours. The reaction mixture was poured into cold water, and extractedwith ethyl acetate. The extract was washed with a saturated saline,dried with anhydrous magnesium sulfate, and concentrated to therebyobtain the crude title compound (1.57 g) having the following physicaldata. The obtained compound was used without purification in thesubsequent reaction.

TLC: Rf 0.60 (hexane:ethyl acetate=2:1).

EXAMPLE 4(1) TO EXAMPLE 4(4)

The following compounds of the present invention were obtained in thesame manner as in Example 4 using the compound prepared in Example 3(1)to Example 3(4) instead of the compound prepared in Example 3.

EXAMPLE 4(1)2-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)acetaldehyde

TLC: Rf 0.58 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 9.63(t, J=1.5 Hz,1H), 7.86(d, J=8.1 Hz, 2H), 7.24(d, J=8.1 Hz, 2H), 7.12(dd, J=7.8, 7.8Hz, 1H), 6.83(d, J=7.8 Hz, 1H), 6.73(d, J=7.8 Hz, 1H), 6.02(t, J=4.5 Hz,1H), 4.25(t, J=6.6 Hz, 2H), 3.43(m, 2H), 2.98(t, J=6.6 Hz, 2H), 2.78(t,J=8.4 Hz, 2H), 2.38(s, 3H), 2.36(s, 3H), 2.31(m, 2H).

EXAMPLE 4(2)2-(5-(2-(2-isopropyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)acetaldehyde

TLC: Rf 0.62 (hexane:ethyl acetate=1:1); NMR(CDCl₃): δ 9.64(t, J=2.4 Hz,1H), 7.12(dd, J=7.8, 7.8 Hz, 1H), 6.81(d, J=7.8 Hz, 1H), 6.73(d, J=7.8Hz, 1H), 6.03(dd, J=4.5, 4.5 Hz, 1H), 4.18(t, J=6.6 Hz, 2H),3.48–3.40(m, 2H), 2.99(sept., J=6.9 Hz, 1H), 2.89(t, J=6.6 Hz, 2H),2.77(t, J=8.1 Hz, 2H), 2.36–2.16(m, 2H), 2.25(s, 3H), 1.31(d, J=6.9 Hz,6H).

EXAMPLE 4(3)2-(5-(2-(2-(4-methylpiperazin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)acetaldehyde

TLC: Rf 0.25(methanol:ethyl acetate=1:5); NMR(CDCl₃): δ 9.64(t, J=2.4Hz, 1H), 7.12(dd, J=8.1, 8.1 Hz, 1H), 6.82(d, J=8.1 Hz, 1H), 6.73(d,J=8.1 Hz, 1H), 6.03(brt, 1H), 4.22(t, J=6.9 Hz, 2H), 3.46–3.37(m, 6H),2.96(t, J=6.9 Hz, 2H), 2.78(dd, J=8.4, 8.4 Hz, 2H), 2.51(m, 4H), 2.34(s,3H), 2.26(s, 3H), 2.34–2.23(m, 2H).

EXAMPLE 4(4)2-(5-(2-(2-(piperidin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)acetaldehyde

TLC: Rf 0.57 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 9.64(t, J=2.7 Hz,1H), 7.12(dd, J=8.1, 8.1 Hz, 1H), 6.82(d, J=8.1 Hz, 1H), 6.72(d, J=8.1Hz, 1H), 6.02(dd, J=4.5, 4.5 Hz, 1H), 4.22(t, J=6.9 Hz, 2H), 3.44(m,2H), 3.36(m, 4H), 2.96(t, J=6.9 Hz, 2H), 2.78(dd, J=8.1, 8.1 Hz, 2H),2.36–2.26(m, 2H), 2.25(s, 3H), 1.72–1.54(m, 6H).

REFERENCE EXAMPLE 282-(4-cyclohexylphenyl)-4-(2-((5-(2,2-diethoxyethyl)-7,8-dihydronaphthalen-1-yl)oxy)ethyl)-5-methyloxazole

To an ethanol (7.8 ml) solution of the compound prepared in Example 4,p-toluenesulfonic acid hydrate (300 mg) was added, followed by stirringat 90° C. for 3 hours. The reaction mixture was cooled to roomtemperature, and poured into a cold saturated aqueous sodium hydrogencarbonate solution, followed by extracting with ethyl acetate. Theextract was washed with saturated saline, dried with anhydrous magnesiumsulfate, and concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=15:1 to 9:1) to thereby obtain thetitle compound (1.04 g) having the following physical data.

TLC: Rf 0.38 (hexane:ethyl acetate=5:1); NMR(CDCl₃): δ 7.94–7.84(m, 2H),7.30–7.22(m, 2H), 7.12(dd, J=7.8, 7.8 Hz, 1H), 6.93(d, J=7.8 Hz, 1H),6.79(d, J=7.8 Hz, 1H), 5.97(t, J=4.5 Hz, 1H), 4.64(m, 1H), 4.25(t, J=6.6Hz, 2H), 3.74–3.58(m, 2H), 3.52–3.38(m, 2H), 2.98(t, J=6.6 Hz, 2H),2.80–2.64(m, 4H), 2.53(m, 1H), 2.35(s, 3H), 2.26–2.14(m, 2H),1.96–1.70(m, 5H), 1.52–1.20(m, 5H), 1.16(t, J=6.9 Hz, 6H).

REFERENCE EXAMPLE 293-(5-(2-(2-(4-cyclohexylphenyl)-5-methyloxazol-4-yl)ethoxy)3,4-dihydronaphthalen-1-yl)-2-ethoxypropanenitrile

To a methylene chloride (9.5 ml) solution of the compound (1.00 g)prepared in Reference Example 28, trimethylsilyl cyanide (0.76 ml) andboron trifluoride ethyl ether complex (0.14 ml) was added, followed bystirring at room temperature for 1.5 hours. The reaction mixture waspoured into a cold aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The extract was washed with saturatedsaline, dried with anhydrous magnesium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1 to 7:1) to thereby obtain the crude title compound (837 mg)having the following physical data. The obtained compound was usedwithout purification in the subsequent reaction.

TLC: Rf 0.27 (hexane:ethyl acetate=5:1); NMR(CDCl₃): δ 7.94–7.84(m, 2H),7.32–7.22(m, 2H), 7.14(dd, J=8.4, 8.4 Hz, 1H), 6.88–6.76(m, 2H), 6.09(t,J=4.5 Hz, 1H), 4.32–4.18(m, 3H), 3.80(m, 1H), 3.48(m, 1H), 3.10–2.44(m,7H), 2.36(s, 3H), 2.32–2.10(m, 2H), 1.96–1.70(m, 5H), 1.52–1.14(m, 8H).

EXAMPLE 52-ethoxy-3-(5-(2-(2-(4-cyclohexylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

To an ethanol (11 ml) solution of the compound prepared in ReferenceExample 29, a 5N aqueous sodium hydroxide solution (3.8 ml) was added,followed by stirring at 90° C. for 4 hours. The reaction mixture wascooled to room temperature, poured into cold water, and washed witht-butyl methyl ether. The aqueous layer was neutralized with 2Nhydrochloric acid, and extracted with ethyl acetate. The extract waswashed with saturated saline, dried with anhydrous magnesium sulfate,and concentrated. The residue was purified by silica gel columnchromatography (chloroform: methanol=12:1) to thereby obtain thecompound of the present invention (676 mg) having the following physicaldata.

TLC: Rf 0.42 (chloroform:methanol=8:1); NMR(CDCl₃): δ 7.94–7.84(m, 2H),7.32–7.22(m, 2H), 7.13(dd, J=7.8, 7.8 Hz, 1H), 6.96(d, J=7.8 Hz, 1H),6.80(d, J=7.8 Hz, 1H), 5.98(t, J=4.5 Hz, 1H), 4.24(t, J=6.6 Hz, 2H),4.04(dd, J=8.7, 4.2 Hz, 1H), 3.54(m, 1H), 3.43(m, 1H), 3.06(m, 1H),2.99(t, J=6.6 Hz, 2H), 2.90–2.44(m, 4H), 2.35(s, 3H), 2.26–2.12(m, 2H),1.96–1.68(m, 5H), 1.52–1.16(m, 5H), 1.12(t, J=6.9 Hz, 3H).

EXAMPLE 6(1) TO EXAMPLE 6(4)

The following compounds of the present invention were obtained in thesame manner as in Reference Example 28→Reference Example 29→Example 5using the compound prepared in Example 4(1) to Example 4(4) instead ofthe compound prepared in Example 4.

EXAMPLE 6(1)2-ethoxy-3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.42 (chloroform:methanol=10:1); NMR(CDCl₃): δ 7.86(d, J=8.1 Hz,2H), 7.23(d, J=8.1 Hz, 2H), 7.14(dd, J=7.8, 7.8 Hz, 1H), 6.96(d, J=7.8Hz, 1H), 6.82(d, J=7.8 Hz, 1H), 5.98(t, J=4.5 Hz, 1H), 4.26 & 4.25(eacht, J=6.6 Hz, total 2H), 4.04(dd, J=9.0, 3.9 Hz, 1H), 3.49(m,2H), 3.08(m,1H), 2.99(t, J=6.6 Hz, 2H), 2.86 & 2.81(each t, J=6.6 Hz, total 1H),2.72–2.52(m, 2H), 2.38(s, 3H), 2.36(s, 3H), 2.21(m, 2H), 1.12(t, J=6.9Hz, 3H).

EXAMPLE 6(2)2-ethoxy-3-(5-(2-(2-isopropyl-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid ½ calcium salt

TLC: Rf 0.42 (chloroform:methanol=8:1); NMR(DMSO-d₆): δ 7.07(dd, J=7.8,7.8 Hz, 1H), 6.98(d, J=7.8 Hz, 1H), 6.81(d, J=7.8 Hz, 1H), 5.85(dd,J=4.2, 4.2 Hz, 1H), 4.09(t, J=6.3 Hz, 2H), 3.74–3.46(m, 2H), 3.13(m,1H), 3.02–2.56(m, 5H), 2. 54–2.30(m, 2H), 2.18(s, 3H), 2.16–1.94(m, 2H),1.20(d, J=6.6 Hz, 6H), 0.92(t, J=6.9 Hz, 3H).

EXAMPLE 6(3)2-ethoxy-3-(5-(2-(2-(4-methylpiperazin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.35 (chloroform:methanol=5:1); NMR(CDCl₃+CD₃OD): δ 7.11(dd,J=8.1, 8.1 Hz, 1H), 6.99(d, J=8.1 Hz, 1H), 6.77(d, J=8.1 Hz, 1H),5.98(dd, J=4.2, 4.2 Hz, 1H), 4.22(m, 2H), 3.98(dd, J=9.0, 4.5 Hz, 1H),3.66–3.46(m, 5H), 3.44–3.32(m, 1H), 3.02–2.45(m, 10H), 2.52(s, 3H),2.27(s, 3H), 2.22–2.10(m, 2H), 1.10(t, J=6.9 Hz, 3H).

EXAMPLE 6(4)2-ethoxy-3-(5-(2-(2-(piperidin-1-yl)-5-methylthiazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid

TLC: Rf 0.45 (chloroform:methanol=10:1); NMR(CDCl₃): δ 7.12(dd, J=8.1,8.1 Hz, 1H), 6.94(d, J=8.1 Hz, 1H), 6.79(d, J=8.1 Hz, 1H), 5.98(dd,J=4.5, 4.5 Hz, 1H), 4.20(m, 2H), 4.03(dd, J=9.0, 3.9 Hz, 1H), 3.55(m,1H), 3.41(m, 1H), 3.37(m , 4H), 3.06(m, 1H), 2.97(t, J=6.9 Hz, 2H),2.82(ddd, J=15.9, 7.5, 7.5 Hz, 1H), 2.74–2.51(m, 2H), 2.24(s, 3H),2.25–2.14(m, 2H), 1.72–1.55(m, 6H), 1.12(t, J=6.9 Hz, 3H).

EXAMPLE 72-ethoxy-3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanamide

To a mixed solution of3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)-2-ethoxypropanenitrile(146 mg; this compound was prepared in the same manner as in ReferenceExample 28→Reference Example 29 using the compound prepared in Example4(1) instead of the compound prepared in Example 4.) in ethanol (4 ml)and tetrahydrofuran (4 ml), a 5N aqueous sodium hydroxide solution (0.66ml) was added, followed by refluxing for 5 hours. The reaction mixturewas cooled to room temperature, and concentrated. The residue wasdiluted with water. The diluted solution was acidified with 1 Nhydrochloric acid, and extracted with diethyl ether. The extract waswashed with saturated saline, dried with anhydrous magnesium sulfate,and concentrated. The residue was purified by silica gel columnchromatography (chloroform:methanol=50:1 to 30:1). The obtained solidwas recrystallized with a mixed solvent of ethyl acetate and hexane tothereby obtain the compound of the present invention (75 mg) having thefollowing physical data.

TLC: Rf 0.63 (chloroform:methanol=10:1); NMR(CDCl₃): δ 7.86(d, J=8.4 Hz,2H), 7.23(d, J=8.4 Hz, 2H), 7.14(dd, J=7.8, 7.8 Hz, 1H), 7.04(d, J=7.8Hz, 1H), 6.81(d, J=7.8 Hz, 1H), 6.55(br s, 1H), 5.97(t, J=4.5 Hz, 1H),5.37(br s, 1H),4.26 & 4.25(each t, J=6.6 Hz, total 2H),3.88(dd, J=9.6,3.0 Hz, 1H), 3.41(m, 2H), 2.98(t, J=6.6 Hz, 2H), 2.89 & 2.84(each t,J=6.6 Hz, total 1H), 2.62–2.48(m, 2H), 2.38(s, 3H), 2.36(s, 3H), 2.22(m,2H), 1.07(t, J=6.9 Hz, 3H).

REFERENCE EXAMPLE 30N-(1-methyl-1-methoxyethoxy)-3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanamide

To a dimethylformamide (5 ml) solution of the compound (208 mg) preparedin Example 2 and 2-aminooxy-2-methoxypropane (57.7 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg),1-hydroxybenzotriazole (81 mg) and triethylamine (83 μl ) were added,followed by stirring at room temperature overnight. The reaction mixturewas concentrated. The residue was diluted with methylene chloride. Thediluted solution was washed with 1N hydrochloric acid, a saturatedaqueous sodium hydrogen carbonate solution and saturated saline in thisorder, dried with anhydrous sodium sulfate, and concentrated. Theresidue was purified by silica gel column chromatography(chloroform:methanol=50:1) to thereby obtain the title compound (239 mg)having the following physical data.

TLC: Rf 0.44 (chloroform:methanol=10:1); NMR(CDCl₃): δ 7.86(d, J=7.8 Hz,2H), 7.55(s, 1H), 7.23(d, J=7.8 Hz, 2H), 7.13(dd, J=8.4, 8.4 Hz, 1H),6.88(m, 2H), 6.81(d, J=8.4 Hz, 1H), 5.92(m, 1H), 4.24(t, J=6.6 Hz, 2H),3.24(s, 3H), 2.98(t, J=6.6 Hz, 2H), 2.95(s, 3H), 2.88(s, 3H), 2.80(m,2H), 2.70(t, J=8.1 Hz, 2H), 2.38(s, 3H), 2.36(s, 3H), 2.17(m, 2H).

EXAMPLE 8N-hydroxy-3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanamide

To a methanol (2 ml) solution of the compound (239 mg) prepared inReference Example 30, 4N hydrogen chloride-dioxane solution (1.1 ml) wasadded, followed by stirring at room temperature for 1 hour. The reactionmixture was concentrated, and solidified by diethyl ether. The solid wascrystallized with methanol to thereby obtain the compound of the presentinvention (40 mg) having the following physical data.

TLC: Rf 0.48 (chloroform:methanol=10:1); NMR(DMSO-d₆): δ 10.35(s, 1H),7.79(d, J=8.4 Hz, 2H), 7.29(d, J=8.4 Hz, 2H), 7.13(dd, J=8.1, 8.1 Hz,1H), 6.88(m, 2H), 5.82(m, 1H), 4.19(t, J=6.3 Hz, 2H), 2.91(t, J=6.3 Hz,2H), 2.67–2.53(m, 4H), 2.34(s, 3H), 2.33(s, 3H), 2.15–2.03(m, 4H).

EXAMPLE 9N-hydroxy-2-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)acetamide

The compound of the present invention having the following physical datawas obtained in the same manner as in Reference Example 30→Example 8using the compound prepared in Example 2(26) instead of the compoundprepared in Example 2.

TLC: Rf 0.36 (chloroform:methanol=10:1); NMR(DMSO-d₆): δ 10.47(s, 1H),8.73(s, 1H), 7.79(d, J=8.1 Hz, 2H), 7.29(d, J=8.1 Hz, 2H), 7.09(dd,J=7.8, 7.8 Hz, 1H), 6.89(d, J=7.8 Hz, 1H), 6.88(d, J=7.8 Hz, 1H),5.91(t, J=4.5 Hz, 1H), 4.18(t, J=6.3 Hz, 2H), 3.07(s, 2H), 2.91(t, J=6.3Hz, 2H), 2.59(t, J=8.4 Hz, 2H), 2.34(s, 3H), 2.33(s, 3H), 2.13(m, 2H).

EXAMPLE 103-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanamide

Under ice-cooling, to a methylene chloride (15 ml) suspension of thecompound (625 mg) prepared in Example 2, oxalyl chloride (1.31 ml) anddimethylformamide (one drop) were added, followed by stirring at roomtemperature for 2 hours. The reaction mixture was concentrated. Theresidue was subjected to azeotropy with benzene. The obtained oil wasdissolved in tetrahydrofuran (15 ml), and 28% aqueous ammonia was addedthereto until a white precipitate appear, followed by stirring for 30minutes. The reaction mixture was concentrated to thereby obtain thecompound of the present invention (408 mg) having the following physicaldata. The obtained compound was used without purification in thesubsequent reaction.

TLC: Rf 0.38 (chloroform:methanol=10:1); NMR(DMSO-d₆): δ 7.78(d, J=8.4Hz, 2H), 7.29(d, J=8.4 Hz, 2H), 7.13(dd, J=8.7, 8.7 Hz, 1H),6.92–6.85(m, 2H), 6.73(br, 1H), 5.82(t, J=4.5 Hz, 1H), 4.18(t, J=6.3 Hz,2H),2.91(t, J=6.3 Hz, 2H), 2.62–2.52(m, 4H), 2.19(m, 2H), 2.07(m, 2H).

REFERENCE EXAMPLE 313-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanenitrile

To a dioxane (15 ml) solution of the compound prepared in Example 10,pyridine (363 μl) and trifluoroacetic acid (423 μl) were added, followedby stirring at room temperature for 1 hour. The reaction mixture wasconcentrated, and the residue was diluted with ethyl acetate. Thediluted solution was washed with 1 N hydrochloric acid, water and asaturated saline in this order, dried with anhydrous magnesium sulfate,and concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to thereby obtain the titlecompound (533 mg) having the following physical data.

TLC: Rf 0.48 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.86(d, J=8.4 Hz,2H), 7.26(d, J=8.4 Hz, 2H), 7.14(dd, J=7.8, 7.5 Hz, 1H), 6.83(d, J=7.5Hz, ₁H), 6.77(d, J=7.5 Hz, 1H), 5.98(t, J=4.5 Hz, 1H), 4.25(t, J=6.6 Hz,2H), 2,98(t, J=6.6 Hz, 2H), 2.82–2.68(m, 4H), 2.53(t, J=7.8 Hz, 2H),2.38(s, 3H), 2.36(s, 3H), 2.24(m, 2H).

EXAMPLE 115-(2-(5-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)ethyl)-1H-tetrazole

To a toluene (5 ml) solution of the compound (212 mg) prepared inReference Example 31, azidotrimethyltin (163 mg) was added, followed byrefluxing for 6 hours under argon atmosphere. After standing to cool,the reaction mixture was purified by silica gel column chromatography(chloroform:methanol=50:1) to thereby obtain the compound of the presentinvention (83 mg) having the following physical data.

TLC: Rf 0.43 (chloroform:methanol=10:1); NMR(DMSO-d₆): δ 7.79(d, J=8.1Hz, 2H), 7.29(d, J=8.1 Hz, 2H), 7.15(dd, J=7.8, 7.8 Hz, 1H), 6.94(d,J=7.8 Hz, 1H), 6.92(d, J=7.8 Hz, 1H), 5.81(d, J=4.5 Hz, 1H), 4.19(t,J=6.6 Hz, 2H), 3.02(m, 2H), 2.91(t, J=6.6 Hz, 2H), 2.81(t, J=7.5 Hz,2H), 2.54(t, J=8.4 Hz, 2H), 2.33(s, 6H), 2.04(m, 2H).

REFERENCE EXAMPLE 32((5-methoxymethoxy-3,4-dihydronaphthalen-1-yl)methyl)malonic aciddiethyl ester

To an ethanol (1.5 ml) solution of the compound (400 mg) prepared inReference Example 14, malonic acid diethyl ester (0.28 ml) and sodiumethoxide (0.55 ml, 2.6 in EtOH) were added, followed by stirring at 80°C. for 30 minutes. The reaction mixture was cooled to room temperature,and acetic acid and water were added thereto, followed by extractingwith ethyl acetate. The extract was washed with a saturated saline,dried with anhydrous magnesium sulfate, and concentrated to therebyobtain the crude title compound having the following physical data. Theobtained compound was used without purification in the subsequentreaction.

TLC: Rf 0.64 (hexane:ethyl acetate=2:1).

REFERENCE EXAMPLE 33((5hydroxy-3,4-dihydronaphthalen-1-yl)methyl)malonic acid diethyl ester

Under ice-cooling, to an ethanol (5 ml) solution of the compoundprepared in Reference Example 32, 4N hydrogen chloride-ethyl acetatesolution (0.7 ml) was added, followed by stirring at room temperatureovernight. The reaction mixture was concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=10:1to 5:1) to thereby obtain the title compound (428 mg) having thefollowing physical data.

TLC: Rf 0.43 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.06(d, J=7.8 Hz,1H), 6.86(d, J=7.8 Hz, 1H), 6.70(dd, J=7.8, 0.8 Hz, 1H), 5.93(brt, J=4.6Hz, 1H), 5.27(brs, 1H), 4.19(q, J=7.2 Hz, 4H), 3.63(t, J=7.8 Hz, 1H),3.06(dd, J=7.8, 1.0 Hz, 2H), 2.67(t, J=7.8 Hz, 2H), 2.28–2.15(m, 2H),1.25(t, J=7.2 Hz, 6H).

REFERENCE EXAMPLE 34((5-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)methyl)malonicacid diethyl ester

To a methylene chloride (10 ml) solution of the compound (456 mg)prepared in Reference Example 33 and the compound (373 mg) prepared inReference Example 27, triphenylphosphine (561 mg) and1,1′-(azodicarbonyl)dipiperidine (539 mg) were added, followed bystirring at room temperature overnight. The reaction mixture wasconcentrated. Diethyl ether was added to the residue, and an insolublewas removed by filtration. The filtrate was concentrated. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=6:1). The obtained solid was recrystallized with diisopropylether to thereby obtain the title compound (422 mg) having the followingphysical data.

TLC: Rf 0.54 (hexane:ethyl acetate=2:1); NMR(CDCl₃): δ 7.86(d, J=8.1 Hz,2H), 7.23(d, J=8.1 Hz, 2H), 7.13(dd, J=7.5, 7.5 Hz, 1H), 6.88(d, J=7.5Hz, 1H), 6.81(d, J=7.5 Hz, 1H), 5.91(t, J=4.5 Hz, 1H), 4.29(t, J=6.6 Hz,2H), 4.17(q, J=7.2 Hz, 2H), 4.16(q, J=7.2 Hz, 2H), 3.59(t, J=7.5 Hz,1H), 3.05(t, J=7.8 Hz, 2H), 2.98(t, J=6.6 Hz, 2H), 2.38(s, 3H), 2.35(s,3H), 2.16(m, 2H), 1.23(t, J=7.2 Hz, 6H).

EXAMPLE 124-((5-(2-(5-methyl-2-(4-methylphenyl)oxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)methyl)isooxazolidin-3,5-dione

To an anhydrous methanol (10 ml) solution of hydroxyamine hydrochloride(87.5 mg), a methanol solution of sodium methylate (542 μl, 25 wt %) wasadded under argon atmosphere, followed by stirring at room temperaturefor 5 minutes. An insoluble was removed. To the filtrate, an anhydroustetrahydrofuran (5 ml) of the compound (434 mg) prepared in ReferenceExample 34 was added under argon atmosphere, followed by stirring at 60°C. for 6 hours. The reaction mixture was concentrated. The residue wasdiluted with 1N hydrochloric acid. The diluted solution was extractedwith a mixed solvent of diethyl ether and tetrahydrofuran. The extractwas dried with anhydrous magnesium sulfate, and concentrated. Theresidue was recrystallized with methanol to thereby obtain the compoundof the present invention (123 mg) having the following physical data.

TLC: Rf 0.36 (chloroform:methanol:acetic acid=20:2:1); NMR(DMSO-d₆): δ7.79(d, J=8.4 Hz, 2H), 7.29(d, J=8.4 Hz, 2H), 7.12(dd, J=7.8, 7.8 Hz,1H), 6.98(d, J=7.8 Hz, 1H), 6.89(d, J=7.8 Hz, 1H), 5.66(t, J=4.5 Hz,1H), 4.18(t, J=6.3 Hz, 2H), 3.08(br s, 2H), 2.91(t, J=6.3 Hz, 2H),2.56(t, J=8.1 Hz, 2H), 2.33(s, 3H), 2.32(s, 3H), 2.09(m, 2H).

FORMULATION EXAMPLE Formulation Example 1

The following components were admixed in a conventional method andpunched out to obtain 100 tablets each containing 50 mg of the activeingredient.

3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4- 5.0 gdihydronaphthalen-1-yl)propanoic acid Carboxymethyl cellulose calcium(disintegrating agent) 0.2 g Magnesium stearate (lubricant) 0.1 gMicrocrystalline cellulose 4.7 g

Formulation Example 2

The following components were admixed in a conventional method, and thesolution was sterilized in a conventional method, placed at 5 ml intoampoules and freeze-dried in a conventional method to thereby obtain 100ampoules each containing 20 mg of the active ingredient.

3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-  2.0 gdihydronaphthalen-1-yl)propanoic acid Mannitol   20 g Distilled water 1000 ml

1. A compound3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid or a nontoxic salt thereof.
 2. A compound3-(5-(2-(2-(4-methylphenyl)-5-methyloxazol-4-yl)ethoxy)-3,4-dihydronaphthalen-1-yl)propanoicacid.